amyloid-beta-peptides and Cognition-Disorders

Many stroke patients have pre-existing cognitive impairment. Plasma amyloid β peptides (Aβ) - possible biomarkers of Alzheimer's pathology - induce vascular dysfunction. Our objective was to evaluate factors influencing plasma Aβ1-40 and Aβ1-42 peptides in a cohort of stroke patients. In the Biostroke study (ClinicalTrials.gov Identifier: NCT00763217), we collected vascular risk factors, neuroimaging features and biological tests including Aβ1-40 and Aβ1-42. We used the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) to systematically assess the pre-existing cognitive status. Of 403 patients (371 ischemia), 25 met criteria for pre-existing dementia, 142 for pre-existing cognitive decline-no-dementia, and 236 had no PCoI. Aβ1-42 was independently associated with PCoI (odds ratio 0.973; 95% confidence interval: 0.950-0.996; p=0.024). Factors associated with plasma Aβ1- 40 were age, smoking and diabetes mellitus. After exclusion of hemorrhagic strokes, the results remained unchanged, but blood samples taken less than 12 hours after onset were associated with lower plasma Aβ1-40. Our results support a dissociated response of the 2 plasma Aβ peptides in stroke patients, plasma Aβ1-40 being involved in vascular aspects whereas Aβ1-42 might be involved in neurodegenerative processes.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Cognition Disorders; Cohort Studies; Female; Humans; Male; Peptide Fragments; Statistics, Nonparametric; Stroke

We conducted a meta-analysis of relationships between amyloid burden and cognition in cognitively normal, older adult humans.. Methods of assessing amyloid burden included were CSF or plasma assays, histopathology, and PET ligands. Cognitive domains examined were episodic memory, executive function, working memory, processing speed, visuospatial function, semantic memory, and global cognition. Sixty-four studies representing 7,140 subjects met selection criteria, with 3,495 subjects from 34 studies representing independent cohorts. Weighted effect sizes were obtained for each study. Primary analyses were conducted limiting to independent cohort studies using only the most common assessment method (Pittsburgh compound B). Exploratory analyses included all assessment methods.. Episodic memory (r = 0.12) had a significant relationship to amyloid burden. Executive function and global cognition did not have significant relationships to amyloid in the primary analysis of Pittsburgh compound B (r = 0.05 and r = 0.08, respectively), but did when including all assessment methods (r = 0.08 and r = 0.09, respectively). The domains of working memory, processing speed, visuospatial function, and semantic memory did not have significant relationships to amyloid. Differences in the method of amyloid assessment, study design (longitudinal vs cross-sectional), or inclusion of control variables (age, etc.) had little influence.. Based on this meta-analytic survey of the literature, increased amyloid burden has small but nontrivial associations with specific domains of cognitive performance in individuals who are currently cognitively normal. These associations may be useful for identifying preclinical Alzheimer disease or developing clinical outcome measures.

Topics: Aging; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Cognition; Cognition Disorders; Cohort Studies; Cross-Sectional Studies; Female; Humans; Male; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Thiazoles

Disease modifying drugs for Alzheimer's disease (AD) are likely to be most effective when given in non-demented subjects. In this review we summarized biomarkers in cerebrospinal fluid (CSF) and blood that can predict AD-type dementia in subjects with mild cognitive impairment (MCI). In addition, we investigated whether these markers could reduce sample size and costs if used to select subjects for trials on the prevention of AD in subjects with MCI. A meta-analysis of markers that had been investigated in multiple studies showed that the combination of amyloid-beta (Abeta1-42 and tau in CSF had the best predictive accuracy for AD (odds ratio (OR) 18.1, 95% confidence interval (CI) 9.6-32.4). Abeta1-42, total tau, and phosphorylated tau in CSF also predicted conversion, but with lower accuracy (OR 7.5 to 8.1). Plasma levels of Abeta1-40, Abeta1-42, the ratio Abeta1-42/Abeta1-40 and homocysteine did not predict outcome. In a fictive trial design, the use of the combination of Abeta1-42 and tau in CSF in the selection of subjects could reduce sample size by 67% and trial costs by 60% compared to a trial in which unselected subjects with MCI would be enrolled. In conclusion, the combination of Abeta1-42 and tau in CSF is useful to select subjects for trials that aim to slow down the progression from MCI to AD-type dementia.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Clinical Trials as Topic; Cognition Disorders; Disease Progression; Homocysteine; Humans; Lipid Metabolism; Peptide Fragments; tau Proteins

Few public health problems have captured the attention of the biomedical and lay communities alike as has Alzheimer Disease (AD). Several questions remain still open in disease management, as the necessity to delineate disease process from "normal ageing". In the last few years, Mild Cognitive Impairment (MCI) has received significant attention, thus it represents the major risk factor for AD. Not all people diagnosed as having MCI, however, will develop AD, hence there is a need to reliably predict progression. To this aim, different biomarkers have been proposed with the attempt to identify MCI people who already have pre-clinical AD. Neuropsychological assessment, peripheral and CSF biomarkers as well as neuroimaging findings (both structural and functional) have reported variable accuracy values, but better results have been obtained by combined biomarker approach. In this review, we summarise the most recent findings on combined biomarkers and their usefulness in clinical practice for the early and preclinical diagnosis of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognition Disorders; Fluorodeoxyglucose F18; Humans; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Proteome; Serum Amyloid A Protein; tau Proteins

To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab, an anti-β-amyloid (Aβ) antibody, in patients with mild-to-moderate Alzheimer's disease. Cognitive measures were also obtained.. In this phase 2, randomized, double-blind, placebo-controlled clinical trial, 52 patients with Alzheimer's disease received placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and cerebrospinal fluid (CSF) examinations were conducted at baseline and after the active treatment period. The Aβ concentrations were measured in plasma and CSF, and the Alzheimer's Disease Assessment Scale-cognitive portion was administered.. Clinical laboratory values, CSF cell counts, and magnetic resonance imaging scans were unchanged by treatment, and no adverse events could be clearly related to antibody administration. Total (bound to antibody and unbound) Aβ(1-40) and Aβ(1-42) in plasma increased in a dose-dependent manner. Antibody treatment similarly increased total Aβ(1-40) and Aβ(1-42) in CSF. For patients taking 400 mg weekly, antibody treatment decreased unbound Aβ(1-40) in CSF (P < .01), but increased unbound Aβ(1-42) in CSF in a dose-dependent manner. The Alzheimer's Disease Assessment Scale-cognitive portion was unchanged after the 12-week antibody administration.. Antibody administration was well tolerated with doses up to 400 mg weekly. The dose-dependent increase in unbound CSF Aβ(1-42) suggests that this antibody may shift Aβ equilibria sufficiently to mobilize Aβ(1-42) from amyloid plaques.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Antibodies, Monoclonal, Humanized; Cognition Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Electroencephalography; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Psychiatric Status Rating Scales; Pyridines; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

PBT2 is a copper/zinc ionophore that rapidly restores cognition in mouse models of Alzheimer's disease (AD). A recent Phase IIa double-blind, randomized, placebo-controlled trial found that the 250 mg dose of PBT2 was well-tolerated, significantly lowered cerebrospinal fluid (CSF) levels of amyloid-beta42, and significantly improved executive function on a Neuro-psychological Test Battery (NTB) within 12 weeks of treatment in patients with AD. In the post-hoc analysis reported here, the cognitive, blood marker, and CSF neurochemistry outcomes from the trial were subjected to further analysis. Ranking the responses to treatment after 12 weeks with placebo, PBT2 50 mg, and PBT2 250 mg revealed that the proportions of patients showing improvement on NTB Composite or Executive Factor z-scores were significantly greater in the PBT2 250 mg group than in the placebo group. Receiver-operator characteristic analyses revealed that the probability of an improver at any level coming from the PBT2 250 mg group was significantly greater, compared to placebo, for Composite z-scores (Area Under the Curve [AUC] =0.76, p=0.0007), Executive Factor z-scores (AUC =0.93, p=1.3 x 10(-9)), and near-significant for the ADAS-cog (AUC =0.72, p=0.056). There were no correlations between changes in CSF amyloid-beta or tau species and cognitive changes. These findings further encourage larger-scale testing of PBT2 for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Area Under Curve; Australia; Clioquinol; Cognition Disorders; Copper; Dose-Response Relationship, Drug; Double-Blind Method; Executive Function; Humans; International Cooperation; Ionophores; Neuropsychological Tests; Peptide Fragments; ROC Curve; Superoxide Dismutase; Superoxide Dismutase-1; Sweden; tau Proteins

Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration improve memory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brain levels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brain within 15 minutes.. We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI). The proportion of verbal information retained after a delay period was the planned primary outcome measure. Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, beta-amyloid, and cortisol.. Twenty-five participants were randomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13) using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and all clinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained at baseline and after 21 days of treatment.. Fasting plasma glucose and insulin were unchanged with treatment. The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group (p = 0.0374). Insulin-treated subjects also showed improved attention (p = 0.0108) and functional status (p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of the beta-amyloid peptide (A beta 40; p = 0.0471) without affecting the longer isoform (A beta 42), resulting in an increased A beta 40/42 ratio (p = 0.0207).. The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders.

Topics: Administration, Intranasal; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Attention; Brain; Cognition Disorders; Disease Progression; Humans; Insulin; Neuroprotective Agents; Neuropsychological Tests; Peptide Fragments; Pilot Projects; Plaque, Amyloid; Treatment Outcome; Verbal Behavior

To observe the effects of modified Wuzi Yanzong Granule (WYG) on memory function and the activity of serum superoxide dismutase (SOD), malondialdehyde (MDA) levels, leukocyte mitochondrial DNA (mtDNA) deletion rate and beta-amyloid protein(1-28) (A beta(1-28)) in patients with mild cognitive impairment (MCI).. Thirty-six patients with MCI were selected based on the internationally recognized Petersen's criteria, and equally and randomly assigned to two groups. The treated group was treated with WYG and the control group was treated with placebo for 3 months. In addition, 20 healthy subjects were included in the study as the normal control group. Changes of memory function, SOD activity, MDA content, leukocyte mtDNA deletion rate and A beta(1-28) content were observed before and after treatment.. Compared with the normal control group, the memory quotient and SOD activity in patients with MCI decreased significantly (P < 0.01), while MDA, A beta(1-28) levels and the leukocyte mtDNA deletion rate increased significantly (P < 0.01). After treatment, levels of memory quotient and serum SOD activity increased while the serum MDA level, leukocyte mtDNA deletion rate and A beta(1-28) level decreased in the treated group compared with those before treatment (P<0.01, P<0.05). Meanwhile, leukocyte mtDNA deletion rate and A beta(1-28) content in the treated group were all lower than those in the control group (P<0.05).. WYG could improve memory function in patients with MCI and the therapeutic mechanism is possibly related to the increased activity of anti-oxidase, the improved free radical metabolism and the alleviation of leukocyte mtDNA oxidation damage. WYG shows clinical significance in delaying the progression of MCI.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Cognition Disorders; Disease Progression; DNA, Mitochondrial; Double-Blind Method; Drug Compounding; Drugs, Chinese Herbal; Female; Humans; Male; Malondialdehyde; Memory; Middle Aged; Oxidative Stress; Peptide Fragments; Phytotherapy; Placebos; Superoxide Dismutase

Cholesterol clearly plays an influential role in promoting the production of amyloid beta (Abeta) and possibly the progression of Alzheimer's Disease (AD). The AD Cholesterol-Lowering Treatment trial (ADCLT; 1 year duration) tested atorvastatin and found significant benefit on measures of cognition and depressive symptoms in treated patients (N = 32) compared to placebo (N = 31). We assessed the circulating levels of Abeta(1-40), Abeta(1-42), ceruloplasmin (copper chaperone), apolipoprotein E and HDL-cholesterol in blood collected at each clinical visit during the ADCLT. We also determined the circulating cholesterol, ceruloplasmin, and Abeta levels in AD and MCI (mild cognitive impairment) patients, and controls (two groups stratified by function; high and low) participating in our Brain Bank Program. Each Brain Bank individual was clinically assessed for performance on the Mini-Mental Status Exam (MMSE), Rey auditory verbal learning test (AVLT), Clock draw, and UPSIT (smell identification test). Among individuals of equal age and education, scores on the MMSE were significantly reduced in AD compared to both MCI and controls, as were scores on the UPSIT. Ability on delayed verbal recall was significantly reduced in AD compared to MCI, and in MCI compared to both control groups. Performance on the Clock draw was similar for AD and MCI patients, but was significantly reduced when comparing MCI to control. Both cholesterol and ceruloplasmin levels were significantly increased in low-function controls compared to the high-function control group, but were not different from levels identified in the MCI and AD patients. Significantly increased levels of Abeta(1-40) occurred in low- compared to high-function controls, with a further significant increase in MCI compared to low-function controls. Circulating Abeta(1-40) levels were decreased in AD compared to MCI. Levels of Abeta(1-42) were not significantly different between the groups. The slight gradual increase in circulating Abeta(1-40) and Abeta(1-42) levels produced by atorvastatin treatment in the ADCLT were not significant compared placebo. There was a trend for significant reduction in circulating ceruloplasmin levels after a year of atorvastatin therapy compared to levels observed at screen. The levels of HDL-cholesterol remained stable in the atorvastatin treated AD patients for 9 months and then decreased significantly compared to the placebo group at the 1-year time-point. The combined data support

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Atorvastatin; Ceruloplasmin; Cholesterol; Cholinergic Antagonists; Cognition Disorders; Copper; Cross-Sectional Studies; Heptanoic Acids; Humans; Longitudinal Studies; Middle Aged; Peptide Fragments; Pyrroles; Verbal Learning

Cerebral microbleeds (MBs) have been found in patients with cognitive decline. We aimed to examine whether MBs are associated with motor or cognitive decline in patients with Parkinson's disease (PD). We enrolled 135 PD patients and 34 healthy controls. All participants underwent brain MRI and plasma biomarker assays, including tau, Aβ42, Aβ40, and α-synuclein. PD with dementia (PDD) was operationally defined as Mini-Mental State Examination (MMSE) score < 26 and advanced motor stage was defined as Hoehn-Yahr stage ≥ 3 during "on" status. The association between MBs and disease severity was examined using multivariate logistic regression models. More lobar MBs were observed in PD patients than controls (20.7% vs. 3.3%, p = 0.031). PDD patients had more lobar MBs (33.3% vs. 15.6%, p = 0.034), more white matter hyperintensity (p = 0.021) and reduced hippocampal volume (p = 0.001) than PD with normal cognition. The presence of lobar MB (odds ratio = 2.83 [95% confidence interval 1.04-7.70], p = 0.042) and severe white matter hyperintensity (3.29 [1.21-8.96], p = 0.020) was independently associated with PDD after adjusting for vascular risk factors and other confounders. Furthermore, plasma Aβ40 levels were associated the MMSE score (p = 0.004) after adjusting for age and sex. Our findings demonstrated that lobar MBs, reduced hippocampal volume, and elevated plasma Aβ40 levels are associated with PDD.

Topics: Aged; Amyloid beta-Peptides; Biomarkers; Case-Control Studies; Cerebral Hemorrhage; Cognition Disorders; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Parkinson Disease; Peptide Fragments; Severity of Illness Index

The complement C1q plays a critical role in microglial phagocytosis of glutamatergic synapses and in the pathogenesis of neuroinflammation in Alzheimer's disease (AD). We recently reported that upregulation of metabotropic glutamate receptor signaling is associated with increased synaptic C1q production and subsequent microglial phagocytosis of synapses in the rodent models of AD. Here, we explored the role of astrocytic glutamate transporter in the synaptic C1q production and microglial phagocytosis of hippocampal glutamatergic synapses in a rat model of AD. Activation of astrocyte and reduction glutamate transporter 1 (GLT1) were noted after bilateral microinjection of amyloid-beta (Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Aspartic Acid; Astrocytes; CA1 Region, Hippocampal; Ceftriaxone; Cognition Disorders; Complement C1q; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Glutamic Acid; Male; Microglia; Morris Water Maze Test; Neurons; Patch-Clamp Techniques; Peptide Fragments; Phagocytosis; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Synapses; Up-Regulation

To enhance the accuracy of clinical diagnosis for Alzheimer's disease (AD), pre-mortem biomarkers have become increasingly important for diagnosis and for participant recruitment in disease-specific treatment trials. Cerebrospinal fluid (CSF) biomarkers provide a low-cost alternative to positron emission tomography (PET) imaging for in vivo quantification of different AD pathological hallmarks in the brains of affected subjects; however, consensus around the best platform, most informative biomarker and correlations across different methodologies are controversial.. Assessing levels of Aβ-amyloid and tau species determined using three different versions of immunoassays, the current study explored the ability of CSF biomarkers to predict PET Aβ-amyloid (32 Aβ-amyloid-and 45 Aβ-amyloid+), as well as concordance between CSF biomarker levels and PET Aβ-amyloid imaging.. Prediction and concordance analyses were performed using a sub-cohort of 77 individuals (48 healthy controls, 15 with mild cognitive impairment, and 14 with AD) from the Australian Imaging Biomarker and Lifestyle study of aging.. Across all three platforms, the T-tau/Aβ42 ratio biomarker had modestly higher correlation with SUVR/BeCKeT (ρ= 0.69-0.8) as compared with Aβ42 alone (ρ= 0.66-0.75). Differences in CSF biomarker levels between the PET Aβ-amyloid-and Aβ-amyloid+ groups were strongest for the Aβ42/Aβ40 and T-tau/Aβ42 ratios (p < 0.0001); however, comparison of predictive models for PET Aβ-amyloid showed no difference between Aβ42 alone and the T-tau/Aβ42 ratio.. This study confirms strong concordance between CSF biomarkers and PET Aβ-amyloid status is independent of immunoassay platform, supporting their utility as biomarkers in clinical practice for the diagnosis of AD and for participant enrichment in clinical trials.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognition Disorders; Female; Humans; Male; Mental Status Schedule; Peptide Fragments; Positron-Emission Tomography; ROC Curve; tau Proteins

To investigate restorative effects of the receptor for advanced glycation end products (RAGE)-specific inhibitor FPS-ZM1 on abnormal amyloid β (Aβ) influx across the blood brain-barrier (BBB) and cognitive deficits in db/db mice.. Aβ influx across the BBB was determined by intra-arterial infusion of. Downregulation of abnormal Aβ influx across the BBB by FPS-ZM1 at higher dosage contributes to reduced neuronal apoptosis, improved hippocampal plasticity and cognitive impairment in db/db mice.

Topics: Amyloid beta-Peptides; Animals; bcl-2-Associated X Protein; Benzamides; Blood-Brain Barrier; Brain; Caspase 3; Cognition Disorders; Diabetes Mellitus, Type 2; Disease Models, Animal; Exploratory Behavior; Male; Maze Learning; Mice; Microvessels; Peptide Fragments; Proto-Oncogene Proteins c-bcl-2; Receptor for Advanced Glycation End Products; Receptors, Leptin; Synaptic Transmission

Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder characterized by pathological hallmarks of beta-amyloid plaque deposits, tau pathology, inflammation, and cognitive decline. Treatment remains a clinical obstacle due to lack of effective therapeutics. Agonists targeting nuclear receptors, such as bexarotene, reversed cognitive deficits regardless of treatment duration and age in murine models of AD. While bexarotene demonstrated marked efficacy in decreasing plaque levels following short-term treatment, prolonged treatment did not modulate plaque burden. This suggested that plaques might reform in mice treated chronically with bexarotene and that cessation of bexarotene treatment before plaques reform might alter amyloid pathology, inflammation, and cognition in AD mice.. We utilized one-year-old APP/PS1 mice that were divided into two groups. We treated one group of mice for 2 weeks with bexarotene. The other group of mice was treated for 2 weeks with bexarotene followed by withdrawal of drug treatment for an additional 2 weeks. Cognition was evaluated using the novel-object recognition test either at the end of bexarotene treatment or the end of the withdrawal period. We then analyzed amyloid pathology and microgliosis at the conclusion of the study in both groups.. Bexarotene treatment enhanced cognition in APP/PS1 mice similar to previous findings. Strikingly, we observed sustained cognitive improvements in mice in which bexarotene treatment was discontinued for 2 weeks. We observed a sustained reduction in microgliosis and plaque burden following drug withdrawal exclusively in the hippocampus.. Our findings demonstrate that bexarotene selectively modifies aspects of neuroinflammation in a region-specific manner to reverse hippocampal-dependent cognitive deficits in AD mice and may provide insight to inform future studies with nuclear receptor agonists.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Newborn; Bexarotene; Cells, Cultured; Cognition; Cognition Disorders; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Transgenic; Peptide Fragments; Plaque, Amyloid; Receptors, Cytoplasmic and Nuclear; Retinoid X Receptors

Alzheimer's disease (AD) is a neurodegenerative disease featured by memory loss, neuroinflammation and oxidative stress. Overproduction or insufficient clearance of Aβ leads to its pathological aggregation and deposition, which is considered the predominant neuropathological hallmark of AD. Therefore, reducing Aβ levels and inhibiting Aβ-induced neurotoxicity are feasible therapeutic strategies for AD treatment. Wolfberry has been traditionally used as a natural antioxidant and anti-aging product. However, whether wolfberry species has therapeutic potential on AD remains unknown.. The effects of fruitless wolfberry-sprout extract (FWE) on Aβ fibrillation and fibril disaggregation was measured by thioflavin T fluorescence and transmission electron microscope imaging; Aβ oligomer level was determined by dot-blot; Cell viability and apoptosis was assessed by MTT and TUNEL assay. The levels of Aβ40/42, oxidative stress biomarkers and inflammatory cytokines were detected by corresponding kits. 8-month-old male APP/PS1 mice and their age-matched WT littermates were treated with FWE or vehicle by oral administration (gavage) once a day for 4 weeks. Then the cognitive performance was determined using object recognition test and Y-maze test. The Aβ burden and gliosis was evaluated by immunostaining and immunoblotting, respectively.. FWE significantly inhibited Aβ fibrillation and disaggregated the formed Aβ fibrils, lowered Aβ oligomer level and Aβ-induced neuro-cytotoxicity, and attenuated oxidative stress in vitro. Oral administration of FWE remarkably improved cognitive function, reduced Aβ burden, decreased gliosis and inflammatory cytokines release, and ameliorated oxidative stress in the brains of APP/PS1 mice.. These findings indicate that FWE is a promising natural agent for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Calcium-Binding Proteins; Cognition Disorders; Disease Models, Animal; Glial Fibrillary Acidic Protein; Glutathione; Glutathione Disulfide; Interleukin-6; Lycium; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Mutation; Oxidative Stress; Peptide Fragments; Plant Extracts; Presenilin-1; Recognition, Psychology; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The objective of the study is to measure plasma and exosomal levels of tau, phosphorylated tau (p-tau), and amyloid beta (Aβ) in Veterans with historical mild traumatic brain injury (mTBI) and chronic neuropsychological symptoms.. Tau, p-tau, Aβ40, and Aβ42 were measured by ultrasensitive immunoassay in plasma and exosomes from 195 Veterans enrolled in the Chronic Effects of Neurotrauma Consortium Multicenter Observational Study. Protein biomarkers were compared among groups with and without mTBI with loss of consciousness (LOC) or post-traumatic amnesia (PTA), and also in those with and without repetitive (≥3) mTBI (rTBI) compared to those with 0 (TBI-neg) and 1-2 mTBI.. There were no differences in measures of plasma and exosomal protein levels among mTBI with LOC or PTA, mTBI with alteration of consciousness only or TBI-neg. Exosomal tau and exosomal p-tau were elevated in rTBI compared to those with 2 or fewer mTBIs and TBI-neg (p < 0.05). Elevations of exosomal tau and p-tau significantly correlated with post-traumatic and post-concussive symptoms, with exosomal tau also relating specifically to cognitive, affective, and somatic post-concussive symptoms (p < 0.05).. rTBI is associated with elevations of exosomal p-tau and exosomal tau, suggesting that blood-based exosomes may provide a peripheral source of informative, centrally derived biomarkers in remote mTBI and that rTBI may contribute to chronic neuropsychological symptoms.

Topics: Adult; Amyloid beta-Peptides; Brain Concussion; Brain Injury, Chronic; Cognition Disorders; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Mood Disorders; Peptide Fragments; Phosphorylation; Surveys and Questionnaires; tau Proteins; Veterans

Ubiquilin-1 (Ubqln1) is a ubiquitin-like protein that has been implicated in Alzheimer's disease (AD). However, whether Ubqln1 modulates learning and memory and alters AD-like behavior and/or pathology has not been determined in animal models. To understand the function of Ubqln1 in vivo, we previously generated Ubqln1 transgenic (TG) mice that overexpress mouse Ubqln1. With the model, we here characterized the TG mouse cognitive behaviors and found that Ubqln1 TG mice showed better spatial learning and memory capabilities than their wild-type littermates in both radial arm water maze and Y-maze tests. Additionally, we crossed the Ubqln1 TG mice with the AβPPswe/PSEN1dE9 double transgenic AD mouse to generate the AD/Ubqln1 triple TG (AD/TG) mice. Our results suggest that at 12 months of age following the onset of AD, AD/TG mice showed better spatial learning and memory than AD mice. AD/TG mice also exhibited better motor function than AD mice at the same age. Furthermore, compared to AD mice, AD/TG mice showed significant reduction in amyloid-β 40 (Aβ40) and Aβ42 levels in the cerebral cortex and in the hippocampus at the post-onset stage. The number of Aβ plaques was significantly decreased in the cerebral cortex of AD/TG mice at this post-onset stage. Moreover, mature AβPP level in AD/TG hippocampus was lower than that in AD hippocampus. These data not only provide a direct link between overexpression of Ubqln1 and altered learning and memory, but also raise the possibility that Ubqln1 is a potential therapeutic target for treating AD and possibly other neurodegenerative disorders.

Topics: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Autophagy-Related Proteins; Brain; Cognition Disorders; Disease Models, Animal; Gene Expression Regulation; Hand Strength; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Movement Disorders; Mutation; Peptide Fragments; Presenilin-1; Rotarod Performance Test

Clusterin and beta-amyloid (Aβ) are involved in the pathogenesis of Alzheimer's disease (AD). The clinical significance of plasma clusterin and Aβ in AD progression remains controversial.. We recruited 322 patients with AD and 88 controls between August 2012 and June 2013. All participants were evaluated at baseline with a clinical assessment, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR) scales. Patients with AD were evaluated annually with the MMSE and Neuropsychiatric Inventory (NPI) scale during the 2-year follow-up period. The levels of plasma clusterin, Aβ1-40, and Aβ1-42 at baseline were analyzed to study the longitudinal changes in the patient scores on the MMSE and NPI during the follow-up period.. Patients in the highest tertile of plasma clusterin levels showed significantly lower MMSE scores than those in the lowest tertile (p = 0.04). After adjustment for multiple covariates using the generalized estimating equation analysis, there was a significant decrease in the MMSE scores over the 2-year follow-up period among AD patients in the highest tertile of plasma clusterin levels compared with those in the lowest tertile (-2.09, 95% confidence interval (CI) = -3.67 to -0.51, p = 0.01). In apolipoprotein E (ApoE)4-positive AD patients, baseline measurements of the ratio of plasma Aβ1-42/Aβ1-40 in the highest tertile predicted an increase in NPI agitation/aggression scores over the 2-year follow-up period (6.06, 95% CI = 1.20-10.62, p = 0.02).. Plasma clusterin could serve as a biomarker for the severity of cognitive decline. Plasma Aβ in ApoE4-positive AD could predict long-term agitation/aggression symptoms.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Clusterin; Cognition Disorders; Disease Progression; Female; Humans; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Psychiatric Status Rating Scales; Statistics, Nonparametric

Kai Xin San (KXS), a traditional formula of Chinese medicine, has been used to treat dementia.. The present study aimed to investigate its ameliorating effects on Aβ. Rats were pretreated with KXS aqueous extract (0.72 and 1.44g/kg, p.o.) for 10 days, and were trained to gain reward reinforcement by lever pressing at the meantime. Thereafter, rats received a bilateral microinjection of Aβ. Our findings first demonstrated that KXS can improve Aβ. In conclusion, KXS has the potential to prevent and/or delay the deterioration of cognitive impairment in AD.

Topics: Acetylcholine; Amyloid beta-Peptides; Animals; Behavior, Animal; Cognition; Cognition Disorders; Drugs, Chinese Herbal; Glutamic Acid; Hippocampus; Learning; Male; Neuroprotective Agents; Peptide Fragments; Phytotherapy; Rats, Wistar; Reward

Amyloid β (Aβ) peptide aggregating to form a neurotoxic plaque, leading to cognitive deficits, is believed to be one of the plausible mechanisms for Alzheimer's disease (AD). Inhibiting Aβ aggregation is supposed to offer a neuroprotective effect to ameliorate AD. A previous report has shown that SLM, a carbazole-based fluorophore, binds to Aβ to inhibit the aggregation. However, it is not entirely clear whether the inhibition of Aβ aggregation alone would lead to the anticipated neuroprotective effects. In the current study, we intended to examine the protective action of SLM against Aβ-induced neurotoxicity in vitro and to evaluate if SLM can decrease the cognitive and behavioral deficits observed in triple transgenic AD mouse model (3xTg-AD). In the in vitro study, neurotoxicity induced by Aβ42 in human neuroblastoma (SH-SY5Y) cells was found to be reduced through the treatment with SLM. In the in vivo study, following one month SLM intraperitoneal injection (1, 2, and 4 mg/kg), 3xTg-AD mice were tested on Morris water maze (MWM) and Y-maze for their cognitive ability and sacrificed for biochemical estimations. Results show that SLM treatment improved the learning and memory ability in 3xTg-AD mice in MWM and Y-maze tasks. SLM also mitigated the amyloid burden by decreasing brain Aβ40 and Aβ42 levels and reduced tau phosphorylation, glycogen synthase kinase-3β activity, and neuro-inflammation. From our observations, SLM shows neuroprotection in SH-SY5Y cells against Aβ42 and also in 3xTg-AD mouse model by mitigating the pathological features and behavioral impairments.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Carbazoles; Cell Death; Cell Line, Tumor; Cognition Disorders; Gene Expression Regulation; Humans; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroblastoma; Neuroprotective Agents; Peptide Fragments; Plaque, Amyloid; Presenilin-1; tau Proteins

In the brain, amyloid-beta generation participates in the pathophysiology of cognitive disorders; in the bloodstream, the role of amyloid-beta is uncertain but may be linked to sterile inflammation and senescence. We explored the relationship between blood levels of amyloid-beta 1-40 peptide (Aβ40), cognition, and mortality (all-cause, cardiovascular, and heart failure [HF]-related) in ambulatory patients with HF.. Bloodstream Aβ40 was measured in 939 consecutive patients with HF. Cognition was evaluated with the Pfeiffer questionnaire (adjusted for educational level) at baseline and during follow-up. Multivariate Cox regression analyses and measurements of performance (discrimination, calibration, and reclassification) were used, with competing risk for specific causes of death.. Over 5.1 ± 2.9 years, 471 patients died (all-cause): 250 from cardiovascular causes and 131 HF-related. The median Aβ40 concentration was 519.1 pg/mL [Q1-Q3: 361.8-749.9 pg/mL]. The Aβ40 concentration correlated with age, body mass index, renal dysfunction, and New York Heart Association functional class (all P < .001). There were no differences in Aβ40 in patients with and without cognitive impairment at baseline (P = .97) or during follow-up (P = .20). In multivariable analysis, including relevant clinical predictors and N-terminal pro-B-type natriuretic peptide, Aβ40 remained significantly associated with all-cause death (HR, 1.22; 95%CI, 1.10-1.35; P < .001) and cardiovascular death (HR, 1.18; 95%CI, 1.03-1.36; P = .02), but not with HF-related death (HR, 1.13; 95%CI, 0.93-1.37; P = .22). Circulating Aβ40 improved calibration and patient reclassification.. Blood levels of Aβ40 are not associated with cognitive decline in HF. Circulating Aβ40 was predictive of mortality and may indicate systemic aging.

Topics: Aged; Amyloid beta-Peptides; Biomarkers; Cognition Disorders; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis

The pathogenesis of Alzheimer's disease (AD) is strongly correlated with the aggregation and deposition of the amyloid beta (Aβ1-42) peptide in fibrillar form, and many studies have shown that plant-derived polyphenols are capable of attenuating AD progression in various disease models. In this study, we set out to correlate the effects of anthocyanoside extracts (Vaccinium myrtillus anthocyanoside (VMA)) obtained from bilberry on the in vitro progression of Aβ fibril formation with the in vivo effects of this compound on AD pathogenesis.. Thioflavin T fluorescence assays and atomic force microscopy were used to monitor Aβ amyloid formation in in vitro assays. Effects of Aβ amyloids on cellular viability were assayed using cultured Neuro2a cells. Cognitive effects were probed using mice that simultaneously expressed mutant human Aβ precursor and mutant presenilin-2.. Addition of VMA inhibited the in vitro formation of Aβ peptide fibrils and also reduced the toxicity of these aggregates toward Neuro2a cells. A diet containing 1% VMA prevented the cognitive degeneration in AD mice. Curiously, this diet-derived retention of cognitive ability was not accompanied by a reduction in aggregate deposition in brains; rather, an increase in insoluble deposits was observed compared with mice raised on a control diet.. The paradoxical increase in insoluble deposits caused by VMA suggests that these polyphenols divert Aβ aggregation to an alternate, non-toxic form. This finding underscores the complex effects that polyphenol compounds may exert on amyloid deposition in vivo.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Anthocyanins; Benzothiazoles; Brain; Cell Line, Tumor; Cognition; Cognition Disorders; Female; Humans; Male; Mice; Microscopy, Atomic Force; Peptide Fragments; Plant Extracts; Polyphenols; Thiazoles; Vaccinium myrtillus

Age is the major risk factor for developing Alzheimer's disease (AD), and modifying age-related factors may help to delay the onset of the disease. The goal of this study was to investigate the relationship between age and the metabolic factors related to the risk of developing AD. The concentrations of insulin, amylin, and amyloid-β peptide (Aβ) in plasma were measured. We further measured the activity of serum Aβ degradation by using fluorescein- and biotin-labeled Aβ40. Apolipoprotein E4 allele (ApoE4) and cognitive impairment were characterized. Subjects were divided into three age groups: 60-70, 70-80, and ≥80 years old. We found that the older the subjects, the lower the concentration of insulin (p = 0.001) and the higher the concentration of Aβ1-40 (p = 0.004) in plasma. However, age was not associated with the concentration of another pancreatic peptide, amylin, and only marginally with Aβ1-42. These relationships remained in the absence of diabetes, cardiovascular disease, and stroke, and regardless of the presence of ApoE4 and cognitive impairment. Both age and ApoE4 were inversely associated with, while insulin was positively associated with, the activities of Aβ degradation in serum. Our study suggested that low concentration of insulin and high concentration of Aβ40 are aging factors related to the risk of AD.

Topics: Age Distribution; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Cognition Disorders; Cross-Sectional Studies; Female; Humans; Insulin; Islet Amyloid Polypeptide; Linear Models; Male; Middle Aged; Multivariate Analysis; Peptide Fragments

Cognitive impairment in hemodialysis patients is common, but the underlying pathogenesis remains unclear. Alzheimer's disease is the most common cause of dementia in the general elderly population. Histopathological hallmarks are, among others, senile plaques, which consist of amyloid-β (Aβ).. To measure plasma levels of Aβ42 and Aβ40 during hemodialysis and to examine potential associations with cognitive performance in cognitively impaired hemodialysis patients.. Plasma samples of 26 hemodialysis patients were collected shortly before, after 50% of dialysis time, and at the end of a dialysis session. Aβ42 and Aβ40 levels were measured by a high-sensitivity ELISA for human amyloid-β. Cognition was tested under standardized conditions using the Montreal Cognitive Assessment (MoCA) as proposed previously.. Clearance rates of both peptides during one dialysis session were 22% and 35% for Aβ42 and Aβ40, respectively. Aβ42 but not Aβ40 baseline levels were significantly associated with MoCA test results (r = 0.654, p = 0.001).. In cognitively impaired hemodialysis patients plasma Aβ42 levels were associated with cognitive performance and both Aβ42 and Aβ40 plasma levels could be effectively reduced by dialysis. By inducing peripheral Aβ sink, hemodialysis may be considered as an anti-amyloid treatment strategy.

Topics: Adult; Aged; Aged, 80 and over; Amyloid beta-Peptides; Cognition Disorders; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Peptide Fragments; Renal Dialysis

Increasing evidence suggests that Alzheimer's disease begins at least a decade before the diagnosis of dementia. Earlier identification of the disease will have important implications for intervention; however, current models of preclinical changes are theoretical and require verification from empirical observations. Furthermore, these models have not incorporated psychiatric features.. Clinical and biological markers were examined at baseline (1999-2001) in 9,076 people aged 65 years and older. A nested case-control study included 830 cases with Alzheimer's disease diagnosed by DSM-IV criteria during the 10-year follow-up and twice as many controls. By taking the distance between baseline and diagnosis as the length of the preclinical period, disease marker trajectories were estimated using nonparametric locally weighted smoothing analysis.. Significant differences for the cases compared to the controls were observed on both intercept and slope for truncated amyloid β40 (P = .006; P = .003, respectively), C-reactive protein (P = .03; P = .05), verbal fluency (P < .0001; P < .0001), visual recall (P < .0001; P = .007), and hippocampal volume (P = .0002; P = .04) and on the slope only for truncated amyloid β42 (P = .01). The cases showed higher levels of depressive symptoms (P = .003), which remained stable over the 10 years to diagnosis.. As hypothesized by existing theoretical models, changes in plasma amyloid β levels, hippocampal atrophy, cognitive loss, and C-reactive protein are already observed up to 10 years before diagnosis. An acceleration in cognitive decline appears to follow a significant increase in amyloid accumulation, and depressive symptomatology remains at a constantly higher level. Overall, clinical and biological markers do not follow the same trajectories; the clinical picture changes according to distance from dementia.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; C-Reactive Protein; Cognition Disorders; Depression; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Neuroimaging; Peptide Fragments; Prodromal Symptoms; White Matter

The neuropathological hallmarks of Alzheimer's disease (AD) are extracellular plaques built up by the accumulation of the amyloid-β protein precursor (AβPP)-derived peptide β (Aβ), and intracellular tangles of hyperphosphorylated tau protein. Sirtuin 2 (SIRT2) is a member of the sirtuin family, featuring conserved enzymes with deacetylase activity and involved in several cell molecular pathways. We investigated the importance of SIRT2 inhibition in AD. We inhibited SIRT2 by small molecules (AGK-2, AK-7) and examined AβPP metabolism in H4-SW neuroglioma cells overexpressing AβPP and two AD transgenic mouse models (3xTg-AD and APP23). The in vitro studies suggested that the inhibition of SIRT2 reduced Aβ production; in vivo data showed an improvement of cognitive performance in the novel object recognition test, and an effect on AβPP proteolytic processing leading to a reduction of soluble β-AβPP and an increase of soluble α-AβPP protein. In 3xTg-AD mice, we noticed that total tau protein level rose. Overall, our pre-clinical data support a role for SIRT2 inhibition in the improvement of cognitive performance and the modulation of molecular mechanisms relevant for AD, thus deserving attention as possible therapeutic strategy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Benzamides; Brain; Calcium-Binding Proteins; Cell Line, Tumor; Cognition Disorders; Disease Models, Animal; Enzyme Inhibitors; Furans; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Glioma; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Peptide Fragments; Phosphorylation; Quinolines; Sirtuin 2; Sulfonamides

Intraneuronal accumulation of abnormally hyperphosphorylated tau in the brain is a histopathological hallmark of Alzheimer's disease and a family of related neurodegenerative disorders collectively called tauopathies. At present there is no effective treatment available for these progressive neurodegenerative diseases which are clinically characterized by dementia in mid to old-age. Here we report the treatment of 14-17-months-old 3xTg-AD mice with tau antibodies 43D (tau 6-18) and 77E9 (tau 184-195) to the N-terminal projection domain of tau or mouse IgG as a control by intraperitoneal injection once a week for 4 weeks, and the effects of the passive immunization on reduction of hyperphosphorylated tau, Aβ accumulation and cognitive performance in these animals. We found that treatment with tau antibodies 43D and 77E9 reduced total tau level, decreased tau hyperphosphorylated at Ser199, Ser202/Thr205 (AT8), Thr205, Ser262/356 (12E8), and Ser396/404 (PHF-1) sites, and a trend to reduce Aβ pathology. Most importantly, targeting N-terminal tau especially by 43D (tau 6-18) improved reference memory in the Morris water maze task in 3xTg-AD mice. We did not observe any abnormality in general physical characteristics of the treated animals with either of the two antibodies during the course of this study. Taken together, our studies demonstrate for the first time (1) that passive immunization targeting normal tau can effectively clear the hyperphosphorylated protein and possibly reduce Aβ pathology from the brain and (2) that targeting N-terminal projection domain of tau containing amino acid 6-18 is especially beneficial. Thus, targeting selective epitopes of N-terminal domain of tau may present a novel effective therapeutic opportunity for Alzheimer disease and other tauopathies.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Antibodies; Cognition Disorders; Disease Models, Animal; Female; Humans; Immunization, Passive; Maze Learning; Mice, Transgenic; Peptide Fragments; Phosphorylation; Plaque, Amyloid; Presenilin-1; tau Proteins

Aβ-induced neuronal toxicity and memory loss is thought to be dependent on neuroinflammation, an important event in Alzheimer's disease (AD). Previously, we demonstrated that the blockage of the kinin B2 receptor (B2R) protects against the memory deficits induced by amyloid β (Aβ) peptide in mice. In this study, we aimed to investigate the role of B2R on Aβ-induced neuroinflammation in mice and the beneficial effects of B2R blockage in synapses alterations.. The selective kinin B2R antagonist HOE 140 (50 pmol/site) was given by intracerebroventricular (i.c.v.) route to male Swiss mice 2 h prior the i.c.v. injection of Aβ(1-40) (400 pmol/site) peptide. Animals were sacrificed, at specific time points after Aβ(1-40) injection (6 h, 1 day or 8 days), and the brain was collected in order to perform immunohistochemical analysis. Different groups of animals were submitted to behavioral cognition tests on day 14 after Aβ(1-40) administration.. In this study, we report that the pre-treatment with the selective kinin B2R antagonist HOE 140 significantly inhibited Aβ-induced neuroinflammation in mice. B2R antagonism reduced microglial activation and the levels of pro-inflammatory proteins, including COX-2, iNOS and nNOS. Notably, these phenomena were accompanied by an inhibition of MAPKs (JNK and p38) and transcription factors (c-Jun and p65/NF-κB) activation. Finally, the anti-inflammatory effects of B2R antagonism provided significant protection against Aβ(1-40)-induced synaptic loss and cognitive impairment in mice.. Collectively, these results suggest that B2R activation may play a critical role in Aβ-induced neuroinflammation, one of the most important contributors to AD progression, and its blockage can provide synapses protection.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Cerebral Cortex; Cognition Disorders; Cyclooxygenase 2; Disease Models, Animal; Drug Administration Schedule; Hippocampus; Imidazoles; Male; Mice; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Peptide Fragments; Spatial Memory; Spiro Compounds; Time Factors; Up-Regulation

Subclinical vitamin C deficiency is widespread in many populations, but its role in both Alzheimer's disease and normal aging is understudied. In the present study, we decreased brain vitamin C in the APPSWE/PSEN1deltaE9 mouse model of Alzheimer's disease by crossing APP/PSEN1(+) bigenic mice with SVCT2(+/-) heterozygous knockout mice, which have lower numbers of the sodium-dependent vitamin C transporter required for neuronal vitamin C transport. SVCT2(+/-) mice performed less well on the rotarod task at both 5 and 12 months of age compared to littermates. SVCT2(+/-) and APP/PSEN1(+) mice and the combination genotype SVCT2(+/-)APP/PSEN1(+) were also impaired on multiple tests of cognitive ability (olfactory memory task, Y-maze alternation, conditioned fear, Morris water maze). In younger mice, both low vitamin C (SVCT2(+/-)) and APP/PSEN1 mutations increased brain cortex oxidative stress (malondialdehyde, protein carbonyls, F2-isoprostanes) and decreased total glutathione compared to wild-type controls. SVCT2(+/-) mice also had increased amounts of both soluble and insoluble Aβ1-42 and a higher Aβ1-42/1-40 ratio. By 14 months of age, oxidative stress levels were similar among groups, but there were more amyloid-β plaque deposits in both hippocampus and cortex of SVCT2(+/-)APP/PSEN1(+) mice compared to APP/PSEN1(+) mice with normal brain vitamin C. These data suggest that even moderate intracellular vitamin C deficiency plays an important role in accelerating amyloid pathogenesis, particularly during early stages of disease development, and that these effects are likely modulated by oxidative stress pathways.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anxiety; Ascorbic Acid; Ascorbic Acid Deficiency; Brain; Cognition Disorders; Disease Models, Animal; Female; Learning; Male; Memory; Mice, Transgenic; Motor Activity; Oxidative Stress; Peptide Fragments; Presenilin-1; Sodium-Coupled Vitamin C Transporters

Cholinergic dysfunction and oxidation stress are the dominant mechanisms of memory deficit in Alzheimer's disease (AD). This study describes how ferulic acid (FA) ameliorates cognitive deficits induced by mecamylamine (MECA), scopolamine (SCOP), central acetylcholinergic neurotoxin ethylcholine mustard aziridinium ion (AF64A) and amyloid β peptide (Aβ1-40). This study also elucidates the role of anti-oxidant enzymes and cholinergic marker acetylcholinesterase (AChE) in the reversal of FA from Aβ1-40-induced cognitive deficits in rats. At 100 mg/kg, FA attenuated impairment induced by MECA and SCOP plus MECA; however, this improvement was not blocked by the peripheral muscarinic receptor antagonist scopolamine methylbromide (M-SCOP). At 100 and 300 mg/kg, FA also attenuated the impairment of inhibitory passive avoidance induced by AF64A. Further, FA attenuated the performance impairment and memory deficit induced by Aβ1-40 in rats, as did vitamin E/C. FA reversed the deterioration of superoxide dismutase (SOD) and AChE activities, and the glutathione disulfide (GSSG) and glutathione (GSH) levels in the cortex and hippocampus. Vitamin E/C only selectively reversed deterioration in the hippocampus. We suggest that FA reduced the progression of cognitive deficits by activating central muscarinic and nicotinic receptors and anti-oxidant enzymes.

Topics: Acetylcholinesterase; Amyloid beta-Peptides; Animals; Antioxidants; Cerebral Cortex; Cholinergic Agents; Cognition Disorders; Coumaric Acids; Disease Models, Animal; Hippocampus; Learning; Male; Peptide Fragments; Rats, Sprague-Dawley; Receptors, Muscarinic; Receptors, Nicotinic; Superoxide Dismutase

Deposition of amyloid-β (Aβ) peptides into specific encephalic structures has been pointed as an important event related to Alzheimer's disease pathogenesis and associated with activation of glial cells, neuroinflammation, oxidative responses, and cognitive deficits. Aβ-induced pro-oxidative damage may regulate the activity of glutamate transporters, leading to reduced glutamate uptake and, as a consequence, excitotoxic events. Herein, we evaluated the effects of the pretreatment of atorvastatin, a HMG-CoA reductase inhibitor, on behavioral and biochemical alterations induced by a single intracerebroventricular (i.c.v.) injection of aggregated Aβ1-40 in mice. Atorvastatin (10 mg/kg/day, p.o.) was administered through seven consecutive days before Aβ1-40 administration. Aβ1-40 caused significant cognitive impairment in the object-place recognition task (2 weeks after the i.c.v. injection) and this phenomenon was abolished by atorvastatin pretreatment. Ex vivo evaluation of glutamate uptake into hippocampal and cerebral cortices slices showed atorvastatin, and Aβ1-40 decreased hippocampal and cortical Na(+)-dependent glutamate uptake. However, Aβ1-40 increased Na(+)-independent glutamate uptake and it was prevented by atorvastatin in prefrontal cortex slices. Moreover, Aβ1-40 treatment significantly increased the cerebrocortical activities of glutathione reductase and glutathione peroxidase and these events were blunted by atorvastatin pretreatment. Reduced or oxidized glutathione levels were not altered by Aβ1-40 and/or atorvastatin treatment. These results extend the notion of the protective action of atorvastatin against neuronal toxicity induced by Aβ1-40 demonstrating that a pretreatment with atorvastatin prevents the spatial learning and memory deficits induced by Aβ in rodents and promotes changes in glutamatergic and antioxidant systems mainly in prefrontal cortex.

Topics: Acetylcholinesterase; Amyloid beta-Peptides; Animals; Atorvastatin; Cognition Disorders; Glutamic Acid; Hippocampus; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Infusions, Intraventricular; Male; Mice; Oxidative Stress; Peptide Fragments; Prefrontal Cortex; Recognition, Psychology; Spatial Learning; Spatial Memory

Tong Luo Jiu Nao (TLJN), a modern formula of Chinese medicine extracts on the basis of Traditional Chinese Medicine theory, has been used to treat dementia. The present study aimed to investigate its ameliorating effects on Aβ1-40-induced cognitive impairment in rats using a series of novel reward-directed instrumental learning (RDIL) tasks, and to determine its possible mechanism of action.. Rats were pretreated with TLJN extract (0.9 and 1.8 g/kg, p.o.) for 10 daysbefore surgery, and were trained to gain reward reinforcement by lever pressing at the meantime. Thereafter, rats received a bilateral microinjection of Aβ1-40 in CA1 regions of the hippocampus. Cognitive performance was evaluated with the goal directed (higher response ratio) and habit (visual signal discrimination and extinction) learning tasks, as well as on the levels of biochemical parameters and molecules.. Our findings first demonstrated that TLJN can improve Aβ1-40-induced amnesia in RDIL via enhancing the comprehension of action-outcome association and the utilization of cue information to guide behavior. Then, its ameliorating effects should attribute to the modulation of ERK/CaMKII/CREB signaling in the hippocampus.. TLJN can markedly enhance cognitions of Aβ1-40 microinjection animal model in adaptive behavioral tasks. It has the potential, possibly as complementary and alternative therapy, to prevent and/or delay the deterioration of cognitive impairment in AD.

Topics: Adaptation, Psychological; Alzheimer Disease; Amnesia; Amyloid beta-Peptides; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cognition; Cognition Disorders; Cyclic AMP Response Element-Binding Protein; Dementia; Disease Models, Animal; Drugs, Chinese Herbal; Feedback, Psychological; Hippocampus; Learning; Male; MAP Kinase Signaling System; Medicine, Chinese Traditional; Peptide Fragments; Phytotherapy; Rats, Wistar; Signal Transduction

Plasma levels of circulating amyloid-beta (Aβ) peptides are of particular interest in Alzheimer' disease, but little is known about cognitive and cortical correlates of peripheral Aβ levels in normal aging. Here, we compared cognitive functioning, vascular risk factors, and patterns of cortical thickness between cognitively intact elderly subjects with low (N = 60) and high (N = 60) plasma Aβ levels (cutoffs: 225 pg/mL and 23 pg/mL for Aβ1-40 and Aβ1-42, respectively). Overall, subjects with high Aβ levels showed lower cognitive performance and thinner cortex than those with low Aβ levels. More specifically, subjects with high Aβ1-40 showed bilateral thinning of the prefrontal cortex, poorer objective memory, slower processing speed, and lower nonverbal reasoning skills, whereas subjects with high Aβ1-42 had thinner temporal lobe, poorer everyday memory, and increased levels of homocysteine. Overall, these results suggest that high plasma Aβ levels in normal elderly subjects are associated with subclinical markers of vulnerable aging, which may be helpful at predicting different trajectories of aging in cognitively intact older adults.

Topics: Aged; Aging; Alzheimer Disease; Amyloid beta-Peptides; Cerebral Cortex; Cognition; Cognition Disorders; Female; Homocysteine; Humans; Male; Peptide Fragments; Risk Factors

Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by a decline in cognitive abilities and the appearance of β-amyloid plaques in the brain. Although the pathogenic mechanisms associated with AD are not fully understood, activated microglia releasing various neurotoxic factors, including pro-inflammatory cytokines and oxidative stress mediators, appear to play major roles. Here, we investigated the therapeutic benefits of a serum-free conditioned medium (CM) derived from the stem cells of human exfoliated deciduous teeth (SHEDs) in a mouse model of AD. The intranasal administration of SHEDs in these mice resulted in substantially improved cognitive function. SHED-CM contained factors involved in multiple neuroregenerative mechanisms, such as neuroprotection, axonal elongation, neurotransmission, the suppression of inflammation, and microglial regulation. Notably, SHED-CM attenuated the pro-inflammatory responses induced by β-amyloid plaques, and generated an anti-inflammatory/tissue-regenerating environment, which was accompanied by the induction of anti-inflammatory M2-like microglia. Our data suggest that SHED-CM may provide significant therapeutic benefits for AD.

Topics: Administration, Intranasal; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Survival; Cells, Cultured; Cerebral Cortex; Cognition Disorders; Culture Media, Conditioned; Cytokines; Dental Pulp; Disease Models, Animal; Embryo, Mammalian; Glutamic Acid; Humans; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Neurons; Peptide Fragments; Recognition, Psychology; Stem Cells

To obtain the proof of concept of a novel therapy for Alzheimer's disease (AD), we conducted two prospective studies with hemodialysis patients who had amyloid β protein (Aβ) removed from their blood three times a week. One major pathological change in the brain associated with AD is Aβ deposition, mainly 40 amino acids Aβ1-40 and 42 amino acids Aβ1-42. Impaired Aβ clearance is proposed to be one cause of increased Aβ in the AD brain. Thus, we hypothesized that an extracorporeal removal system of Aβ from the blood may remove brain Aβ and be a useful therapeutic strategy for AD. In the first prospective study, plasma Aβ levels and the cognitive function of 30 hemodialysis patients (65-76 years old) were evaluated at baseline as well as 18 or 36 months after. Although plasma Aβ1-40 levels either decreased or remained unchanged, levels of Aβ1-42 either remained unchanged or increased at the second time point. Mini-Mental State Examination scores of most subjects increased or were maintained at the second time point. Aβ1-40 influx into the blood correlated with MMSE at the second time point. In the second prospective study, five patients (51-84 years old) with renal failure were evaluated before and after the initiation of hemodialysis. Plasma Aβ levels decreased, while cognitive function improved after initiating blood Aβ removal. Therefore, long-term hemodialysis, which effectively removes blood Aβ, might alter Aβ influx and help maintain cognitive function.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Brain; Cognition; Cognition Disorders; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peptide Fragments; Positron-Emission Tomography; Prospective Studies; Renal Dialysis; Smoking; Tomography, X-Ray Computed; Treatment Outcome

Luteolin can be found in many traditional Chinese medicines, it's a falconoid compound derived from Lonicera japonica Thunb. This study aims to investigate the neuroprotective effects of luteolin against cognitive impairment induced by amyloid-β (Aβ) peptide and the underlying mechanisms in rats. The animal behavioral tests showed that luteolin could ameliorate Aβ-induced learning and memory impairment. In hippocampal tissue, the activity of choline acetyl transferase (ChAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) increased after treated by luteolin. Luteolin also reversed the increased activity of acetylcholine esterase (AchE). In hippocampi homogenate, the content of acetylcholine (Ach) increased, but malondialdehyde (MDA) reduced. Moreover, luteolin can increase Bcl-2/Bax ratio. This study demonstrated that luteolin could protect Alzheimer's disease (AD) rats against Aβ-induced cognitive impairment through regulating the cholinergic system and inhibiting oxidative injuries. The results suggesting that luteolin may have potential as a therapy for AD.

Topics: Acetylcholinesterase; Amyloid beta-Peptides; Animals; Antioxidants; bcl-2-Associated X Protein; Behavior, Animal; Choline O-Acetyltransferase; Cognition; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione Peroxidase; GPI-Linked Proteins; Hippocampus; Luteolin; Malondialdehyde; Maze Learning; Memory; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Proto-Oncogene Proteins c-bcl-2; Rats, Sprague-Dawley; Superoxide Dismutase

Apolipoprotein E (ApoE) has an active part in the pathogenesis of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) and plasma level alterations have been reported in AD patients. In search of a biomarker potentially predictive of cognitive, functional, or motor decline, we analyzed the CSF to serum ratios of ApoE levels (CSF/serum ApoE) in AD patients in this regard.. Subjects with newly diagnosed AD were followed within a longitudinal observational study (rpAD study). Annual neuropsychological testing and physical examination were performed. Multiple regression analyses were used to determine possible associations of the ApoE CSF/serum concentration ratios and velocity of decline on a variety of cognitive, functional and motor scales (MMSE, iADL, bADL, GDS, UPDRSIII) adjusted for relevant co-variables.. CSF/serum ratios of ApoE levels were associated with progression on the UPDRSIII (change of UPDRSIII slope [pt/yr] per unit of ApoE CSF/serum = -0.06, p <  0.01) and instrumental ADL scale (change of iADL slope [pt/yr] per unit of ApoE CSF/serum = 0.01, p = 0.01) ("the lower the ratio, the faster the deterioration" and vice versa). Secondarily, higher age at onset was associated with faster UPDRSIII progression, antidepressant use with faster iADL decline, and better baseline function with more rapid decline on either MMSE, iADL, or GDS scale.. Here, CSF/serum ApoE at time of AD diagnosis was shown to be inversely associated with medium-term functional and motor progression. Whether this ratio qualifies for the use as a predictive biomarker must be validated in larger cohort studies over the long term.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Cognition Disorders; Female; Humans; Longitudinal Studies; Male; Mental Status Schedule; Middle Aged; Movement Disorders; Peptide Fragments; Severity of Illness Index; tau Proteins

To investigate the effects of sevoflurane inhalation on β-amyloid (Aβ)-induced cognitive disorders and hippocampal oxidative stress in rat models.. Cognitive dysfunction is induced by hippocampal injection of Aβ1-40 (10μg in 2μl) for 22days. To explore the effect of sevoflurane inhalation on Aβ1-40 induced cognitive disorder, two doses of sevoflurane inhalation are used: 1.3% (Aβ+S1) and 2.6% (Aβ+S2). Sham operation (Sham, for operation control), saline injection (Control, for injection control) and 30% oxygen inhalation after Aβ1-40 injection (Aβ+O2, for inhalation control) were used as controls. All rats were further tested in electrical Y-maze and Morris water maze. Serum S100β levels, hippocampal superoxide dismutase (SOD) activity, S100β expression and malonyldialdehyde (MDA) concentrations were further quantified.. Rats in Aβ+O2, Aβ+S1 and Aβ+S2 groups had lower number of correct actions in the electrical Y maze task, longer escape latencies, less time exploring the original platform, elevated serum S100β levels, depressed hippocampal SOD activity, S100β expression and higher MDA concentrations compared to control group (p<0.05). Such difference was not significant between Aβ+S1 and Aβ+O2 rats. Rats in Aβ+S2 group, however, showed significantly impaired performances compared to those in Aβ+S1 group (p<0.05).. Sevoflurane (2.6%) can aggravate the Aβ-induced cognitive dysfunction, possibly via the intracerebral oxidative stress response.

Topics: Amyloid beta-Peptides; Animals; Cognition Disorders; Hippocampus; Male; Methyl Ethers; Oxidative Stress; Peptide Fragments; Rats; Rats, Sprague-Dawley; Sevoflurane

Early-onset familial Alzheimer disease (AD) is an autosomal dominant disorder caused by mutations in the amyloid precursor protein, presenilin 1 (PSEN1), or presenilin 2 gene. The objective of this study was to characterize the phenotype in a large family with a PSEN1 F177S mutation by performing detailed clinical assessments, neuroimaging, and neuropathological analysis.. In two subjects, clinical and neuropsychological assessments, structural magnetic resonance imaging, F-18-2-fluoro-2-deoxy-D-glucose positron emission tomographic imaging, AD biomarkers in cerebrospinal fluid and genetic analysis were available. In three deceased affected subjects, medical records were reviewed. In one subject, a complete neuropathological examination was available.. Cognitive impairment and neurological symptoms developed homogeneously around 30 years of age and worsened rapidly. All subjects died about 7 years (range, 6-8 years) after disease onset before 40 years of age. All technical diagnostic information (neuroimaging, cerebrospinal fluid) were typically for AD. Neuropathology showed abundant neuritic plaques and neurofibrillary tangles, typical of severe AD. Antidementia treatment in one subject did not alter the length of survival.. The PSEN1 F177S mutation leads to typical AD starting at age 30 and a homogeneous phenotype with rapid cognitive decline and prominent neurological symptoms. Excessive amyloid beta 42 production in the brain cortex corresponds well with other PSEN1 mutations.

Topics: Adult; Age of Onset; Aged; Alzheimer Disease; Amyloid beta-Peptides; Brain; Brain Waves; Cognition Disorders; Electroencephalography; Family Health; Female; Genetic Predisposition to Disease; Humans; Male; Mental Status Schedule; Middle Aged; Mutation; Peptide Fragments; Phenylalanine; Positron-Emission Tomography; Presenilin-1; Radiography; Serine

Early-life lead (Pb) exposure induces overexpression of the amyloid beta precursor protein and its amyloid beta product in older rats and primates. We exposed rodents to Pb during different life span periods and examined cognitive function in old age and its impact on biomarkers associated with Alzheimer's disease (AD).. Morris, Y, and the elevated plus mazes were used. Western blot, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay were used to study the levels of AD biomarkers.. Cognitive impairment was observed in mice exposed as infants but not as adults. Overexpression of AD-related genes (amyloid beta precursor protein and β-site amyloid precursor protein cleaving enzyme 1) and their products, as well as their transcriptional regulator-specificity protein 1 (Sp1)-occurred only in older mice with developmental exposure to Pb.. A window of vulnerability to Pb neurotoxicity exists in the developing brain that can influence AD pathogenesis and cognitive decline in old age.

Topics: Aging; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Animals, Newborn; Antimicrobial Cationic Peptides; Aspartic Acid Endopeptidases; Cognition Disorders; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation, Developmental; Humans; Lead; Male; Maze Learning; Mice; Peptide Fragments; RNA, Messenger

Alzheimer's disease (AD) is the most common form of dementia and now represents 50-70% of total dementia cases. Over the last two decades, transthyretin (TTR) has been associated with AD and, very recently, a novel concept of TTR stability has been established in vitro as a key factor in TTR/amyloid-β (Aβ) interaction. Small compounds, TTR stabilizers (usually non-steroid anti-inflammatory drugs), bind to the thyroxine (T4) central binding channel, increasing TTR tetrameric stability and TTR/Aβ interaction. In this work, we evaluated in vivo the effects of one of the TTR stabilizers identified as improving TTR/Aβ interaction, iododiflunisal (IDIF), in Aβ deposition and other AD features, using AβPPswe/PS1A246E transgenic mice, either carrying two or just one copy of the TTR gene (AD/TTR+/+ or AD/TTR+/-, respectively), available and characterized in our laboratory. The results showed that IDIF administered orally bound TTR in plasma and stabilized the protein, as assessed by T4 displacement assays, and was able to enter the brain as revealed by mass spectrometry analysis of cerebrospinal fluid. TTR levels, both in plasma and cerebrospinal fluid, were not altered. In AD/TTR+/- mice, IDIF administration resulted not only in decreased brain Aβ levels and deposition but also in improved cognitive function associated with the AD-like neuropathology in this mouse model, although no improvements were detectable in the AD/TTR+/+ animals. Further, in AD/TTR+/- mice, Aβ levels were reduced in plasma suggesting TTR promoted Aβ clearance from the brain and from the periphery. Taken together, these results strengthen the importance of TTR stability in the design of therapeutic drugs, highlighting the capacity of IDIF to be used in AD treatment to prevent and to slow the progression of the disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cognition Disorders; Diflunisal; Humans; Maze Learning; Mice; Mice, Transgenic; Nootropic Agents; Peptide Fragments; Plaque, Amyloid; Prealbumin; Presenilin-1

Traumatic brain injury (TBI) is a recognized risk factor for later development of neurodegenerative disease. However, the mechanisms contributing to neurodegeneration following TBI remain obscure.. In this study, we have utilized a novel mild TBI (mTBI) model to examine the chronic neurobehavioral and neuropathological outcomes following single and repetitive mTBI at time points from 6 to 18 months following injury.. Our results reveal that at 6, 12, and 18 months after injury, animals exposed to a single mTBI have learning impairments when compared to their sham controls without exhibiting spatial memory retention deficits. In contrast, animals exposed to repetitive injury displayed persistent cognitive deficits, slower rate of learning, and progressive behavioral impairment over time. These deficits arise in parallel with a number of neuropathological abnormalities, including progressive neuroinflammation and continuing white matter degradation up to 12 months following repetitive injury. Neither single nor repetitive mTBI was associated with elevated brain levels of amyloid beta or abnormal tau phosphorylation at 6 or 12 months after injury.. Importantly, these data provide evidence that, although a single mTBI produces a clinical syndrome and pathology that remain static in the period following injury, repetitive injuries produce behavioral and pathological changes that continue to evolve many months after the initial injuries. As such, this model recapitulates many aspects described in human studies of TBI, providing a suitable platform on which to investigate the evolving pathologies following mild TBI and potential strategies for therapeutic intervention.

Topics: Amyloid beta-Peptides; Animals; Anxiety; Brain Injuries; Cognition Disorders; Corpus Callosum; Disease Models, Animal; Gene Expression Regulation; Male; Maze Learning; Mice; Mice, Inbred C57BL; Movement Disorders; Nerve Fibers, Myelinated; Peptide Fragments; Retention, Psychology; Rotarod Performance Test; tau Proteins; Time Factors

The advent of brain stimulation techniques to treat movement disorders and psychiatric diseases has shown potential to decode the neural mechanism that underlies the cognitive process by modulating the interrupted circuit. Here, the present investigation aimed at evaluating the influence of deep brain stimulation of the anterior nucleus thalamus (ANT-DBS) on memory.. Thirty-two rats were randomized into phosphate buffer saline (PBS) group (n = 8, rats received PBS injections without implantation of electrodes into the ANT), Alzheimer's dementia (AD) group (n = 8, rats received Aβ1-40 injections without implantation of electrodes into the ANT), ANT sham stimulation group (n = 8, rats received Aβ1-40 injections with implantation of electrodes into the ANT but without stimulation) and ANT stimulation group (n = 8, rats received Aβ1-40 injections with implantation of electrodes into the ANT and stimulation). A Morris maze test was used for determining the effect of electrical stimulation on cognitive function in rats. The data were assessed statistically with one-way analysis of variance (ANOVA) followed by Tukey's tests for multiple post hoc comparisons.. The data showed that in the training test, PBS group and AD group managed to learn the hidden-platform faster and faster while AD group needed a significantly longer time to reach the platform than PBS group (P < 0.05). Meanwhile, ANT stimulation group demonstrated a significantly shorter time to reach the platform (P < 0.05) compared to the AD group, while there was no significant difference between the ANT sham stimulation group and the AD group (P > 0.05). On the probe test, the AD group spent less time ((10.15 ± 2.34) seconds) in the target quadrant than the PBS group ((28.20 ± 2.75) seconds) (P < 0.05). And the times of platform-traversing of the AD group (3.35 ± 1.12) significantly decreased compared with the PBS group (8.69 ± 2.87) (P < 0.05). However, the times of platform-traversing and the time spent in the target quadrant of the ANT stimulation group significantly increased compared to the AD group (P < 0.05), while times of platform-traversing or the time spent in the target quadrant was not significantly different between the ANT sham stimulation group and the AD group (P > 0.05).. Bilateral high-frequency stimulation of the ANT may be useful as a potential therapeutic modality for cognitive dysfunction in AD.

Topics: Amyloid beta-Peptides; Animals; Anterior Thalamic Nuclei; Cognition; Cognition Disorders; Deep Brain Stimulation; Hippocampus; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley

Histone deacetylase 6 (HDAC6) is currently being discussed as a promising therapeutic target for the treatment of Alzheimer's disease (AD). Mounting evidence indicates that increased HDAC6 expression may contribute to AD-associated neurodegeneration, although beneficial effects have also been identified. In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-β (Aβ) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aβ and hyperphosphorylated tau. Further, the decreased hyperphosphorylated tau and increased tubulin acetylation may account for the improved microtubule stability in AD mice after tubastatin A/ACY-1215 treatment. These preclinical results support the detrimental role of HDAC6 in AD, and offer prospective approaches for using tubastatin A/ACY-1215 as potential therapeutic strategy for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cognition Disorders; Disease Models, Animal; Exploratory Behavior; Gene Expression Regulation; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Indoles; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Phosphorylation; Presenilin-1; Pyrimidines; Tubulin

Numerous studies have implicated the abnormal accumulation of intraneuronal amyloid-β (Aβ) as an important contributor to Alzheimer's disease (AD) pathology, capable of triggering neuroinflammation, tau hyperphosphorylation and cognitive deficits. However, the occurrence and pathological relevance of intracellular Aβ remain a matter of controversial debate. In this study, we have used a multidimensional approach including high-magnification and super-resolution microscopy, cerebro-spinal fluid (CSF) mass spectrometry analysis and ELISA to investigate the Aβ pathology and its associated cognitive impairments, in a novel transgenic rat model overexpressing human APP. Our microscopy studies with quantitative co-localization analysis revealed the presence of intraneuronal Aβ in transgenic rats, with an immunological signal that was clearly distinguished from that of the amyloid precursor protein (APP) and its C-terminal fragments (CTFs). The early intraneuronal pathology was accompanied by a significant elevation of soluble Aβ42 peptides that paralleled the presence and progression of early cognitive deficits, several months prior to amyloid plaque deposition. Aβ38, Aβ39, Aβ40 and Aβ42 peptides were detected in the rat CSF by MALDI-MS analysis even at the plaque-free stages; suggesting that a combination of intracellular and soluble extracellular Aβ may be responsible for impairing cognition at early time points. Taken together, our results demonstrate that the intraneuronal development of AD-like amyloid pathology includes a mixture of molecular species (Aβ, APP and CTFs) of which a considerable component is Aβ; and that the early presence of these species within neurons has deleterious effects in the CNS, even before the development of full-blown AD-like pathology.

Topics: Acoustic Stimulation; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Brain; Cognition Disorders; Conditioning, Psychological; Disease Models, Animal; Fear; Gene Expression Regulation; Humans; Intracellular Fluid; Mutation; Pain Measurement; Peptide Fragments; Rats; Rats, Transgenic; Recognition, Psychology; Regression Analysis

Neuroinflammation mediated by overactivated microglia plays a key role in many neurodegenerative diseases, including Alzheimer's disease (AD). In this study, we investigated for the first time the anti-neuroinflammatory effects and possible mechanisms of SCM-198 (an alkaloid extracted from Herbaleonuri), which was previously found highly cardioprotective, both in vitro and in vivo.. For in vitro experiments, lipopolysaccharide (LPS) or β-amyloid(1-40) (Aβ(1-40)) was applied to induce microglial overactivation. Proinflammatory mediators were measured and activations of NF-κB and mitogen-activated protein kinases' (MAPKs) pathways were investigated. Further protective effect of SCM-198 was evaluated in microglia-neuron co-culture assay and Sprague-Dawley (SD) rats intrahippocampally-injected with Aβ(1-40).. SCM-198 reduced expressions of nitric oxide (NO), TNF-α, IL-1β and IL-6 possibly via, at least partially, inhibiting c-Jun N-terminal kinase (JNK) and NF-κB signaling pathways in microglia. Co-culture assay showed that activated microglia pretreated with SCM-198 led to less neuron loss and decreased phosphorylation of tau and extracellular signal-regulated kinase (ERK) in neurons. Besides, SCM-198 also directly protected against Aβ(1-40)-induced neuronal death and lactate dehydrogenase (LDH) release in primary cortical neurons. For in vivo studies, SCM-198 significantly enhanced cognitive performances of rats 12 days after intrahippocampal injections of aged Aβ(1-40) peptides in the Morris water maze (MWM), accompanied by less hippocampal microglial activation, decreased synaptophysin loss and phosphorylation of ERK and tau. Co-administration of donepezil and SCM-198 resulted in a slight cognitive improvement in SD rats 50 days after intrahippocampal injections of aged Aβ(1-40) peptides as compared to only donepezil or SCM-198 treated group.. Our findings are the first to report that SCM-198 has considerable anti-neuroinflammatory effects on inhibiting microglial overactivation and might become a new potential drug candidate for AD therapy in the future.

Topics: Amyloid beta-Peptides; Animals; Animals, Newborn; Cell Survival; Cells, Cultured; Cerebral Cortex; Coculture Techniques; Cognition Disorders; Cytokines; Gallic Acid; L-Lactate Dehydrogenase; Male; MAP Kinase Kinase 4; Maze Learning; Microglia; Neurons; Neuroprotective Agents; NF-kappa B; Peptide Fragments; Rats; Rats, Sprague-Dawley; Signal Transduction

The physiological effects of the non-anthocyanin fraction (NAF) in a black soybean seed coat extract on Aβ-induced oxidative stress were investigated to confirm neuroprotection. In addition, we examined the preventive effect of NAF on cognitive defects induced by the intracerebroventricular (ICV) injection of Aβ.. Levels of cellular oxidative stress were measured using 2',7'-dichlorofluorescein diacetate (DCF-DA). Neuronal cell viability was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay. To investigate in vivo anti-amnesic effects of NAF by using Y-maze and passive avoidance tests, the learning and memory impairment in mice was induced by Aβ. After in vivo assays, acetylcholinesterase (AChE) activity and level of malondialdehyde (MDA) in the mouse brain were determined to confirm the cognitive effect. Individual phenolics of NAF were qualitatively analyzed by using an ultra-performance liquid chromatography (UPLC) Accurate-Mass Quadrupole Time of-Flight (Q-TOF) UPLC/MS.. A NAF showed cell protective effects against oxidative stress-induced cytotoxicity. Intracellular ROS accumulated through Aβ1-40 treatment was significantly reduced in comparison to cells only treated with Aβ1-40. In MTT and LDH assay, the NAF also presented neuroprotective effects on Aβ1-40-treated cytotoxicity. Finally, the administration of this NAF in mice significantly reversed the Aβ1-40-induced cognitive defects in in vivo behavioral tests. After behavioral tests, the mice brains were collected in order to examine lipid peroxidation and AChE activity. AChE, preparation was inhibited by NAF in a dose-dependent manner. MDA generation in the brain homogenate of mice treated with the NAF was decreased. Q-TOF UPLC/MS analyses revealed three major phenolics from the non-anthocyanin fraction; epicatechin, procyanidin B1, and procyanidin B2.. The results suggest that the NAF in black soybean seed coat extracts may improve the cytotoxicity of Aβ in PC12 cells, possibly by reducing oxidative stress, and also have an anti-amnesic effect on the in vivo learning and memory deficits caused by Aβ. Q-TOF UPLC/MS analyses showed three major phenolics; (-)-epicatechin, procyanidin B1, and procyanidin B2. Above results suggest that (-)-epicatechins are the major components, and contributors to the anti-amnesic effect of the NAF from black soybean seed coat.

Topics: Acetylcholinesterase; Amyloid beta-Peptides; Animals; Antioxidants; Biflavonoids; Brain; Catechin; Cell Survival; Cognition Disorders; Glycine max; Learning; Learning Disabilities; Male; Memory; Memory Disorders; Mice, Inbred ICR; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Peptide Fragments; Phytotherapy; Plant Extracts; Polyphenols; Proanthocyanidins; Rats; Seeds

Acetylcholinesterase inhibitors (AChEIs), including Huperzine A (HupA), have been the mainstay of treatment for Alzheimer's disease (AD). However, AChEIs can cause gastrointestinal side effects, which has been related to the high Cmax and short tmax after oral administration. Clinical trials have verified that extended-release formulation with lower Cmax and prolonged tmax, such as rivastigmine patch, could perform a similar efficacy with significantly improved tolerability compared with the oral formulations. In this study, we developed an extended-release microspheres formulation of HupA (called as HAM) with poly(lactide-co-glycolide) (PLGA) as drug carrier. HAM has showed the loading rate as 1.35% (w/w) and yielded 42% with mean particle size at 72.6 μm. In vitro and in vivo pharmacokinetics studies have showed that HAM produced a relatively smooth and continuous drug concentration in 14 days. Furthermore, in vivo pharmacokinetics data have demonstrated that the Cmax was lower and the tmax was considerably later in single intramuscular administration of HAM (1,000 μg/kg) than the counterparts in single intragastric administration of HAT (75 μg/kg/d). Meanwhile, HAM has performed a continuous inhibition to brain AChE activity in normal rats and improvement of memory deficit in Aβ1-40 i.c.v. infused AD rat model for 14 days. The results have suggested that HAM has performed good extended-release properties and good prolonged pharmacological efficacy in vivo in the 2-week period, and could exert a similar efficacy with significantly lowered gastrointestinal side effects as compared with oral formulation.

Topics: Acetylcholinesterase; Administration, Oral; Alkaloids; Amyloid beta-Peptides; Animals; Behavior, Animal; Brain; Chemistry, Pharmaceutical; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; GPI-Linked Proteins; Injections, Intramuscular; Lactic Acid; Male; Memory; Microspheres; Particle Size; Peptide Fragments; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Sprague-Dawley; Sesquiterpenes; Technology, Pharmaceutical

The characteristic neuropathological changes associated with Alzheimer's disease (AD) and other lines of evidence support the amyloid cascade hypothesis. Viewing amyloid deposits as the prime instigator of dementia has now led to clinical trials of multiple strategies to remove or prevent their formation. We performed neuropathological and biochemical assessments of 3 subjects treated with bapineuzumab infusions. Histological analyses were conducted to quantify amyloid plaque densities, Braak stages and the extent of cerebral amyloid angiopathy (CAA). Amyloid-β (Aβ) species in frontal and temporal lobe samples were quantified by ELISA. Western blots of amyloid-β precursor protein (AβPP) and its C-terminal (CT) fragments as well as tau species were performed. Bapineuzumab-treated (Bapi-AD) subjects were compared to non-immunized age-matched subjects with AD (NI-AD) and non-demented control (NDC) cases. Our study revealed that Bapi-AD subjects exhibited overall amyloid plaque densities similar to those of NI-AD cases. In addition, CAA was moderate to severe in NI-AD and Bapi-AD patients. Although histologically-demonstrable leptomeningeal, cerebrovascular and neuroparenchymal-amyloid densities all appeared unaffected by treatment, Aβ peptide profiles were significantly altered in Bapi-AD subjects. There was a trend for reduction in total Aβ42 levels as well as an increase in Aβ40 which led to a corresponding significant decrease in Aβ42:Aβ40 ratio in comparison to NI-AD subjects. There were no differences in the levels of AβPP, CT99 and CT83 or tau species between Bapi-AD and NI-AD subjects. The remarkable alteration in Aβ profiles reveals a dynamic amyloid production in which removal and depositional processes were apparently perturbed by bapineuzumab therapy. Despite the alteration in biochemical composition, all 3 immunized subjects exhibited continued cognitive decline.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Antibodies, Monoclonal, Humanized; Brain; Cerebral Amyloid Angiopathy; Cognition Disorders; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunotherapy; Male; Peptide Fragments; tau Proteins; Tomography, X-Ray Computed

Immunotherapy against amyloid-β(Aβ) may improve rodent cognitive function by reducing amyloid neuropathology and is being validated in clinical trials with positive preliminary results. However, for a complete understanding of the direct and long-term immunization responses in the aged patient, and also to avoid significant side effects, several key aspects remain to be clarified. Thus, to investigate brain Aβ clearance and Th2 responses in the elderly, and the reverse inflammatory events not found in the immunized rodent, better Alzheimer's disease (AD) models are required. In the aged familiar canine with a Cognitive Dysfunction Syndrome (CDS) we describe the rapid effectiveness and the full safety profile of a new active vaccine candidate for human AD prevention and treatment. In these aged animals, besidesa weak immune system, the antibody response activated a coordinated central and peripheral Aβ clearance, that rapidly improved their cognitive function in absence of any side effects. Our results also confirm the interest to use familiar dogs to develop innovative and reliable therapies for AD.

Topics: Age Factors; Aging; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Cognition Disorders; Disease Models, Animal; Dogs; Eliminative Behavior, Animal; Expressed Emotion; Female; Hematologic Tests; Humans; Immunoglobulin G; Immunotherapy; Male; Peptide Fragments; Rabbits; Walking

Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer's disease (AD) and might underlie memory impairment. Our previous work demonstrated that the magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we investigated whether elevation of brain magnesium by the use of a recently developed compound, magnesium-l-threonate (MgT), can ameliorate the AD-like pathologies and cognitive deficits in the APPswe/PS1dE9 mice, a transgenic (Tg) mouse model of AD. MgT treatment reduced Aβ plaque and prevented synapse loss and memory decline in the Tg mice. Strikingly, MgT treatment was effective even when given to the mice at the end stage of their AD-like pathological progression. To explore how elevation of brain magnesium ameliorates the AD-like pathologies in the brains of Tg mice, we studied molecules critical for APP metabolism and signaling pathways implicated in synaptic plasticity/density. In the Tg mice, the NMDAR/CREB/BDNF signaling was downregulated, whereas calpain/calcineurin/Cdk5 neurodegenerative signaling and β-secretase (BACE1) expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression, and reduced soluble APPβ and β-C-terminal fragments in the Tg mice. At the molecular level, elevation of extracellular magnesium prevented the high-Aβ-induced reductions in synaptic NMDARs by preventing calcineurin overactivation in hippocampal slices. Correlation studies suggested that the protection of NMDAR signaling might underlie the stabilization of BACE1 expression. Our results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of AD and may have therapeutic potential for treating AD in humans.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Body Weight; Brain; Butyrates; Cognition Disorders; Disease Models, Animal; Exploratory Behavior; Glutamate Decarboxylase; Humans; Magnesium; Male; Maze Learning; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Mutation; Neurons; Neuroprotective Agents; Patch-Clamp Techniques; Peptide Fragments; Presenilin-1; Presynaptic Terminals; Reaction Time; Synapses; Tissue Distribution; Vesicular Acetylcholine Transport Proteins

Alzheimer's disease (AD) is a devastating disorder that is clinically characterized by a comprehensive cognitive decline. Accumulation of the amyloid-beta (Aβ) peptide plays a pivotal role in the pathogenesis of AD. In AD, the conversion of Aβ from a physiological soluble monomeric form into insoluble fibrillar conformation is an important event. The most toxic form of Aβ is oligomers, which is the intermediate step during the conversion of monomeric form to fibrillar form. There are at least two types of oligomers: oligomers that are immunologically related to fibrils and those that are not. In transgenic AD animal models, both active and passive anti-Aβ immunotherapies improve cognitive function and clear the parenchymal accumulation of amyloid plaques in the brain. In this report we studied effect of immunotherapy of two sequence-independent non-fibrillar oligomer specific monoclonal antibodies on the cognitive function, amyloid load and tau pathology in 3xTg-AD mice. Anti-oligomeric monoclonal antibodies significantly reduce the amyloid load and improve the cognition. The clearance of amyloid load was significantly correlated with reduced tau hyperphosphorylation and improvement in cognition. These results demonstrate that systemic immunotherapy using oligomer-specific monoclonal antibodies effectively attenuates behavioral and pathological impairments in 3xTg-AD mice. These findings demonstrate the potential of using oligomer specific monoclonal antibodies as a therapeutic approach to prevent and treat Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antibodies, Monoclonal; Avoidance Learning; Cognition; Cognition Disorders; Disease Models, Animal; Female; Gene Knock-In Techniques; Maze Learning; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Peptide Fragments; Presenilin-1; tau Proteins; Tauopathies; Vaccination

Alzheimer's disease (AD) is characterized by amyloid-β deposition in amyloid plaques, neurofibrillary tangles, inflammation, neuronal loss, and cognitive deficits. Cannabinoids display neuromodulatory and neuroprotective effects and affect memory acquisition. Here, we studied the impact of cannabinoid receptor type 1 (CB1) deficiency on the development of AD pathology by breeding amyloid precursor protein (APP) Swedish mutant mice (APP23), an AD animal model, with CB1-deficient mice. In addition to the lower body weight of APP23/CB1(-/-) mice, most of these mice died at an age before typical AD-associated changes become apparent. The surviving mice showed a reduced amount of APP and its fragments suggesting a regulatory influence of CB1 on APP processing, which was confirmed by modulating CB1 expression in vitro. Reduced APP levels were accompanied by a reduced plaque load and less inflammation in APP23/CB1(-/-) mice. Nevertheless, compared to APP23 mice with an intact CB1, APP23/CB1(-/-) mice showed impaired learning and memory deficits. These data argue against a direct correlation of amyloid plaque load with cognitive abilities in this AD mouse model lacking CB1. Furthermore, the findings indicate that CB1 deficiency can worsen AD-related cognitive deficits and support a potential role of CB1 as a pharmacologic target.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Body Weight; Brain; Cell Line, Tumor; Cognition Disorders; Disease Models, Animal; Gene Expression Regulation; Humans; Maze Learning; Mice; Mice, Transgenic; Microglia; Mutation; Peptide Fragments; Receptor, Cannabinoid, CB1

The peptide amphiphile (PA) with a laminin epitope IKVAV (IKVAV-PA) can be trigged into three-dimensional nanostructures in vivo. Application of IKVAV-PA to the injured spinal cord resulted in significant functional improvement in rodents with remarkable axonal regeneration at the lesion site. Here we showed that injection of IKVAV-PA into the hippocampus of a transgenic (Tg) mice model of Alzheimer's disease (AD) significantly improved cognitive impairment, accompanied by an enhanced neurogenesis in the hippocampus. Further examination demonstrated that IKVAV-PA injections also significantly reduced the levels of soluble Aβ1-40, Aβ1-42, and amyloid-beta (Aβ) plaques in these brains. Our data suggest that IKVAV-PA may serve as a potential therapeutic intervention for the learning and memory losses in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cell Differentiation; Cognition Disorders; Hippocampus; Laminin; MAP Kinase Signaling System; Maze Learning; Memory; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Nanofibers; Neural Stem Cells; Neurogenesis; Neurons; Peptide Fragments; Plaque, Amyloid

Posterior cortical atrophy (PCA) is characterized by progressive higher-order visuo-perceptual dysfunction and praxis declines. This syndrome is related to several underlying diseases, including Alzheimer's disease (AD), sometimes involving an amyloidogenic process. The aims of the study were to 1) define cerebrospinal fluid (CSF) biomarker profiles in PCA patients compared to AD patients and 2) explore the amyloidogenic process through the Aβ(42)/Aβ(40) ratio in PCA patients to elucidate the underlying disease in vivo. CSF biomarker analysis (t-tau, p-tau, Aβ(42), and Aβ(42)/Aβ(40) ratio) and neuropsychological examination were performed in 22 PCA patients and compared with those of age-matched AD patients. Associated clinical neurological signs were investigated (e.g., extrapyramidal motor signs, myoclonus). CSF biomarker profiles did not differ significantly between the PCA and AD groups; 82% of patients with PCA fulfilled the biological criteria for typical AD with abnormal levels of the three markers and 18% of PCA patients presented atypical CSF profiles. All PCA patients with associated clinical neurological signs presented typical AD CSF profiles. The clinical presentations of these patients were similar to other PCA subjects. The Aβ(42)/Aβ(40) ratio for all PCA patients, including those with atypical CSF profiles, was decreased. Most PCA syndromes were associated with CSF biomarkers suggestive of AD, even in cases with associated clinical neurological signs. The amyloidogenic process was confirmed by the decreased Aβ(42)/Aβ(40) ratio for all patients. This analysis avoids misdiagnosis in the presence of physiologically high or low amyloid peptide production rates and provides information in vivo to improve understanding of the underlying disease in PCA.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Cognition Disorders; Female; Humans; Male; Mental Status Schedule; Middle Aged; Peptide Fragments; Perceptual Disorders; Statistics, Nonparametric; tau Proteins

Cerebrospinal fluid (CSF) biomarkers reflect changes in the brain, and contribute to early screening. Maternal inheritance is putatively stronger than paternal inheritance for late-onset Alzheimer's disease (LOAD).. Clinical data of 162 cognitively normal subjects were reviewed. A standard questionnaire was used to identify LOAD family history. Mini-mental state examination (MMSE) was used to evaluate cognition. CSF Aβ1-40, Aβ1-42, total and phosphorylated tau were measured using ELISA.. To compare biomarkers in cognitively normal elderly subjects with versus without LOAD family history.. Among the 162 subjects, 38 and 60 had LOAD family history on paternal and maternal sides, respectively. The remaining 60 subjects had no family history. No difference was noted in age, gender, education level, MMSE score, and memory impairment complaint in the three groups. Aβ42 and the Aβ42/40 ratio were lower than in subjects with a maternal history than in subjects with a paternal history or without family history (P < 0.05 in both). Phosphorylated and total tau did not differ among the three groups.. Offspring with a family history of LOAD on the maternal side have lower Aβ42 and Aβ42/40 ratio in the CSF, and maybe at higher risk for developing AD.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognition Disorders; Cross-Sectional Studies; Family Health; Female; Humans; Linear Models; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Peptide Fragments; Retrospective Studies; tau Proteins

Stress has been described as a risk factor for the development of Alzheimer´s disease (AD). In the present work we aim to study the validity of an experimental model of neonatal chronic stress in order to recapitulate the main hallmarks of AD. Male Wistar rats that were separated daily from the dam during the first 3 weeks of life (maternal separation, MS) showed in adulthood cognitive deficits novel object recognition test. In the hippocampus of MS rats, increases in both Aβ40 and Aβ42 levels, the principal constituent of amyloid plaques observed in AD, were accompanied by increased expression of the cleaving enzyme BACE1. Hyperphosphorylation of Tau associated to increased activation of the tau kinase JNK1 was also found. Decreased cell number in the hippocampus was observed in stressed rats, as a consequence of both decreased cell proliferation and increased apoptotic death. Decreases in BDNF and in the synaptic markers synaptophysin and PSD-95 were also found in MS rats. All these effects could be related to an HPA axis hyperactivity, as reflected in significant increases in corticosterone levels and decreases in glucocorticoid receptor expression. Further, SHSY5Y neuroblastoma cells treated with corticosterone showed increased BACE1, pTau and pJNK1 expression. In addition, venlafaxine, an antidepressant able to modulate HPA axis activity, reversed all the above cited deleterious effects of chronic stress, both in vivo and in vitro. It is proposed that the MS model can be considered as an appropriate experimental model for the study of sporadic AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Animals, Newborn; Antidepressive Agents, Second-Generation; Aspartic Acid Endopeptidases; Brain-Derived Neurotrophic Factor; Cell Death; Cell Line, Tumor; Cell Proliferation; Cognition Disorders; Cyclohexanols; Disease Models, Animal; Disks Large Homolog 4 Protein; Female; Gene Expression Regulation; Hippocampus; Humans; Intracellular Signaling Peptides and Proteins; Male; Maternal Deprivation; Membrane Proteins; Mitogen-Activated Protein Kinase 8; Peptide Fragments; Pregnancy; Rats; Rats, Wistar; Recognition, Psychology; Synaptophysin; tau Proteins; Venlafaxine Hydrochloride

Beta amyloid (Aβ)-induced oxidative stress and chronic inflammation in the brain are considered to be responsible for the pathogenesis of Alzheimer's disease (AD). Salidroside, the major active ingredient of Rhodiola crenulata, has been previously shown to have antioxidant and neuroprotective properties in vitro. The present study aimed to investigate the protective effects of salidroside on Aβ-induced cognitive impairment in vivo. Rats received intrahippocampal Aβ1-40 injection were treated with salidroside (25, 50 and 75 mg/kg p.o.) once daily for 21 days. Learning and memory performance were assessed in the Morris water maze (days 17-21). After behavioral testing, the rats were sacrificed and hippocampi were removed for biochemical assays (reactive oxygen species (ROS), superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), acetylcholinesterase (AChE), acetylcholine (ACh)) and molecular biological analysis (Cu/Zn-SOD, Mn-SOD, GPx, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nuclear factor κB (NF-κB), inhibitor of κB-alpha (IκBα), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), receptor for advanced glycation end products (RAGE)). Our results confirmed that Aβ1-40 peptide caused learning and memory deficits in rats. Further analysis demonstrated that the NADPH oxidase-mediated oxidative stress was increased in Aβ1-40-injected rats. Furthermore, NF-κB was demonstrated to be activated in Aβ1-40-injected rats, and the COX-2, iNOS and RAGE expression were also induced by Aβ1-40. However, salidroside (50 and 75 mg/kg p.o.) reversed all the former alterations. Thus, the study indicates that salidroside may have a protective effect against AD via modulating oxidative stress and inflammatory mediators.

Topics: Acetylcholine; Acetylcholinesterase; Amyloid beta-Peptides; Animals; Cognition Disorders; Cyclooxygenase 2; Glucosides; Hippocampus; Inflammation Mediators; Male; Maze Learning; Microinjections; NADPH Oxidases; Neuroprotective Agents; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Peptide Fragments; Phenols; Rats; Reactive Oxygen Species; Receptor for Advanced Glycation End Products; Receptors, Immunologic

Amyloid-β peptide (Aβ), which is generated by the β- and γ-secretase-mediated proteolysis of β-amyloid precursor protein (APP), plays an important role in the pathogenesis of Alzheimer's disease (AD). We recently reported that prostaglandin E(2) (PGE(2) ) stimulates the production of Aβ through both EP(2) and EP(4) receptors and that activation of the EP(4) receptor stimulates Aβ production through endocytosis and activation of γ-secretase. We here found that transgenic mice expressing mutant APP (APP23) mice showed a greater or lesser apparent cognitive deficit when they were crossed with mice lacking EP(2) or EP(4) receptors, respectively. Mice lacking the EP(4) receptor also displayed lower levels of Aβ plaque deposition and less neuronal and synaptic loss than control mice. Oral administration of a specific EP(4) receptor antagonist, AE3-208 to APP23 mice, improved their cognitive performance, as well as decreasing brain levels of Aβ and suppressing endocytosis and activation of γ-secretase. Taken together, these results suggest that inhibition of the EP(4) receptor improves the cognitive function of APP23 mice by suppressing Aβ production and reducing neuronal and synaptic loss. We therefore propose that EP(4) receptor antagonists, such as AE3-208, could be therapeutically beneficial for the prevention and treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Brain; Cognition Disorders; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Naphthalenes; Nerve Tissue Proteins; Peptide Fragments; Phenylbutyrates; rab GTP-Binding Proteins; rab7 GTP-Binding Proteins; Receptors, Prostaglandin E, EP4 Subtype

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss and cognitive impairments. The presence of extracellular senile plaques (mainly composed of amyloid-β (Aβ) peptide) is an important molecular hallmark in AD and neuronal damage has been attributed, at least in part, to Aβ-mediated toxicity. Although the molecular mechanisms involved in the pathogenesis of AD are not yet completely understood, several lines of evidence indicate that oxidative stress and cholesterol dyshomeostasis play crucial roles in mediating the synaptic loss and cognitive deficits observed in AD patients. This study evaluated the effects of Probucol, a phenolic lipid-lowering agent with anti-inflammatory and antioxidant properties, on biochemical parameters related to oxidative stress and synaptic function (hippocampal glutathione and synaptophysin levels; glutathione peroxidase, glutathione reductase and acetylcholinesterase activities; lipid peroxidation), as well as on behavioral parameters related to the cognitive function (displaced and new object recognition tasks) in Aβ-exposed mice. Animals were treated with a single intracerebroventricular (i.c.v.) injection of aggregated Aβ(1-40) (400 pmol/site) and, subsequently, received Probucol (10 mg/kg, i.p.) once a day, during the following 2 weeks. At the end of treatments, Aβ(1-40)-exposed animals showed a significant impairment on learning-memory ability, which was paralleled by a significant decrease in hippocampal synaptophysin levels, as well as by an increase in hippocampal acetylcholinesterase activity. Importantly, Probucol treatment blunted the deleterious effects of Aβ(1-40) on learning-memory ability and hippocampal biochemistry. Although Aβ(1-40) treatment did not change hippocampal glutathione levels and glutathione peroxidase (GPx) and glutathione reductase (GR) activities, Aβ(1-40)-exposed animals showed increased hippocampal lipid peroxidation and this event was completely blunted by Probucol treatment. These findings reinforce and extend the notion of the hazardous effects of Aβ(1-40) toward hippocampal synaptic homeostasis and cognitive functions. In addition, the present results indicate that Probucol is able to counteract the cognitive and biochemical impairments induced by i.c.v. Aβ(1-40) administration in mice. The study is the first to report the protective effects of Probucol (a "non-statin cholesterol-lowering drug") against Aβ(1-40)-induced synaptic and behavioral impairme

Topics: Amyloid beta-Peptides; Animals; Anticholesteremic Agents; Cognition Disorders; Hippocampus; Humans; Lipid Peroxidation; Male; Mice; Neuroprotective Agents; Peptide Fragments; Probucol; Synapses

Amyloid precursor protein (APP) proteolysis is essential for production of amyloid-β (Aβ) peptides that form β-amyloid plaques in brains of Alzheimer disease (AD) patients. Recent focus has been directed toward a group of naturally occurring anti-amyloidogenic polyphenols known as flavonoids. We orally administered the flavonoid tannic acid (TA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated cognitive function and AD-like pathology. Consumption of TA for 6 months prevented transgene-associated behavioral impairment including hyperactivity, decreased object recognition, and defective spatial reference memory, but did not alter nontransgenic mouse behavior. Accordingly, brain parenchymal and cerebral vascular β-amyloid deposits and abundance of various Aβ species including oligomers were mitigated in TA-treated PSAPP mice. These effects occurred with decreased cleavage of the β-carboxyl-terminal APP fragment, lowered soluble APP-β production, reduced β-site APP cleaving enzyme 1 protein stability and activity, and attenuated neuroinflammation. As in vitro validation, we treated well characterized mutant human APP-overexpressing murine neuron-like cells with TA and found significantly reduced Aβ production associated with less amyloidogenic APP proteolysis. Taken together, these results raise the possibility that dietary supplementation with TA may be prophylactic for AD by inhibiting β-secretase activity and neuroinflammation and thereby mitigating AD pathology.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cell Line; Cerebral Amyloid Angiopathy; Cognition Disorders; Disease Models, Animal; Encephalitis; Female; Gliosis; Humans; Male; Maze Learning; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Peptide Fragments; Tannins

Epidemiological study reveals that socially isolated persons have increased risk of developing Alzheimer's disease (AD). Whether this risk arises from an oxidative stress is unclear. Here we show that N-acetylcysteine (NAC), an anti-oxidant, is capable of preventing social isolation-induced accelerated impairment of contextual fear memory and rundown of hippocampal LTP in 3-month old APP/PS1 mice. Increased hippocampal levels of γ-secretase activity, Aβ-40 and Aβ-42 seen in the isolated APP/PS1 mice were reduced by chronic treatment of NAC. In addition, social isolation-induced increase in calpain activity and p25/p35 ratio concomitant with decrease in membrane-associated p35 and p35/Cdk5 activity was normalized by NAC. NAC pretreatment also reversed isolation-induced decrease in GluR1 Ser831 phosphorylation, surface expression of AMPARs and p35-GluR1-CaMKII interactions. These results suggest that NAC decreases γ-secretase activity resulting in the attenuation of Aβ production, calpain activity and conversion of p35 to p25 which stabilized p35-GluR1-CaMKII interactions and restored GluR1 and GluR2 surface expression. Our results indicate that NAC is effective in mouse models of AD and has translation potential for the human disorder.

Topics: Acetylcysteine; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Antioxidants; Biophysics; Biotinylation; Calpain; Cell Line, Transformed; Cognition Disorders; Conditioning, Psychological; Cyclin-Dependent Kinase 5; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Enzyme-Linked Immunosorbent Assay; Fear; Hippocampus; Humans; In Vitro Techniques; Long-Term Potentiation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Patch-Clamp Techniques; Peptide Fragments; Presenilin-1; Protein Kinase C-delta; Receptors, Metabotropic Glutamate; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Social Isolation; Time Factors; Transfection

Fucoidan is a complex sulfated polysaccharide, derived from marine brown seaweed. In the present study, we investigated the effects of fucoidan on improving learning and memory impairment in rats induced by infusion of Aβ (1-40), and its possible mechanisms. The results indicated that fucoidan could ameliorate Aβ-induced learning and memory impairment in animal behavioral tests. Furthermore, fucoidan reversed the decreased activity of choline acetyl transferase (ChAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and content of acetylcholine (Ach), as well as the increased activity of acetylcholine esterase (AchE) and content of malondialdehyde (MDA) in hippocampal tissue of Aβ-injected rats. Moreover, these were accompanied by an increase of Bcl-2/Bax ratio and a decrease of caspase-3 activity. These results suggested that fucoidan could ameliorate the learning and memory abilities in Aβ-induced AD rats, and the mechanisms appeared to be due to regulating the cholinergic system, reducing oxidative stress and inhibiting the cell apoptosis.

Topics: Acetylcholine; Acetylcholinesterase; Amyloid beta-Peptides; Animals; Apoptosis; Avoidance Learning; bcl-2-Associated X Protein; Behavior, Animal; Caspase 3; Choline O-Acetyltransferase; Cognition; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Glutathione Peroxidase; GPI-Linked Proteins; Hippocampus; Male; Malondialdehyde; Memory; Motor Activity; Neuroprotective Agents; Nootropic Agents; Oxidative Stress; Peptide Fragments; Phaeophyceae; Polysaccharides; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reaction Time; Superoxide Dismutase

Chamaecyparis obtusa Sieb. & Zucc., Endlicher (Cupressaceae) forest bathing or aromatherapy has been shown in various studies to have biological functions such as anticancer, antiallergies, antiinflammatory, and antioxidant activity. However, no reports exist on the pharmacological or biological activities of the essential oil of C. obtusa (EOCO) or its effects on central nervous system.. The aggregation and formation of β-amyloid peptides (Aβ) into fibrils are central events in the pathogenesis of Alzheimer's disease (AD), and overproduction and aggregation of Aβ into oligomers have been known to trigger neurotoxicity. In this study, we investigated the effects of inhaled EOCO on cognitive function and neuronal apoptosis in rats intrahippocampally injected with Aβ.. To model AD, 4 μg of aggregated Aβ was injected into the hippocampus. To test the effects of EOCO, behavioral performance in the Morris water maze was tested 4 days after injection. After behavioral testing, brain sections were prepared for TTC staining and TUNEL assay.. Inhaled EOCO protected spatial learning and memory from the impairments induced by Aβ(1-40) injection. In addition, the behavioral deficits accompanying Aβ(1-40)-induced AD were attenuated by inhalation of EOCO. Furthermore, acetylcholinesterase (AChE) activity and neuronal apoptosis were significantly inhibited in rats treated with Aβ(1-40) and EOCO compared to rats treated only with Aβ(1-40).. EOCO suppressed both AD-related neuronal cell apoptosis and AD-related dysfunction of the memory system. Thus, the results of this study support EOCO as a candidate drug for the treatment of AD.

Topics: Administration, Inhalation; Amyloid beta-Peptides; Animals; Chamaecyparis; Cognition Disorders; Male; Maze Learning; Oils, Volatile; Peptide Fragments; Plant Extracts; Plant Leaves; Random Allocation; Rats; Rats, Sprague-Dawley

The cellular prion protein (PrP(C)) is a neuronal-anchored glycoprotein that has been associated with several functions in the CNS such as synaptic plasticity, learning and memory and neuroprotection. There is great interest in understanding the role of PrP(C) in the deleterious effects induced by the central accumulation of amyloid-β (Aβ) peptides, a pathological hallmark of Alzheimer's disease, but the existent results are still controversial. Here we compared the effects of a single intracerebroventricular (i.c.v.) injection of aggregated Aβ(1-40) peptide (400pmol/mouse) on the spatial learning and memory performance as well as hippocampal cell death biomarkers in adult wild type (Prnp(+/+)), PrP(C) knockout (Prnp(0/0)) and the PrP(C) overexpressing Tg-20 mice. Tg-20 mice, which present a fivefold increase in PrP(C) expression in comparison to wild type mice, were resistant to the Aβ(1-40)-induced spatial learning and memory impairments as indicated by reduced escape latencies to find the platform and higher percentage of time spent in the correct quadrant during training and probe test sessions of the water maze task. The protection against Aβ(1-40)-induced cognitive impairments observed in Tg-20 mice was accompanied by a significant decrease in the hippocampal expression of the activated caspase-3 protein and Bax/Bcl-2 ratio as well as reduced hippocampal cell damage assessed by MTT and propidium iodide incorporation assays. These findings indicate that the overexpression of PrP(C) prevents Aβ(1-40)-induced spatial learning and memory deficits in mice and that this response is mediated, at least in part, by the modulation of programed cell death pathways.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cell Survival; Cognition Disorders; Gene Expression Regulation; Hippocampus; In Vitro Techniques; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Peptide Fragments; Prion Proteins; Prions; Propidium; Proto-Oncogene Proteins c-bcl-2; Reaction Time; Tetrazolium Salts; Thiazoles

Oxidative stress and neuroinflammation play important roles in Alzheimer's disease (AD). ABCG2 is a transporter protein expressed in the brain and involved in GSH transport. To study the roles of Abcg2 in oxidative stress and AD, we cross-bred Tg-SwDI and Abcg2-KO mice and generated Tg-SwDI/Abcg2-KO (double-tg) mice. Brain tissues from double-tg, Tg-SwDI, wild-type, and Abcg2-KO mice at various ages were analyzed. Aβ40 and Aβ42 were detected in Tg-SwDI and double-tg mice. Total brain GSH was decreased and levels of lipid/DNA oxidation were increased in 3-month double-tg compared to Tg-SwDI mice. Low brain GSH was still detected in 9-month double-tg mice. Increased HMOX-1 and MCP-5 expression was observed in 9-month double-tg mice but not in Tg-SwDI mice compared to WT and Abcg2-KO mice. Increased HMOX-1 and decreased ICAM-1 expression were observed in 12-month double-tg mice compared to Tg-SwDI mice. The levels of Nrf-2 expression and activity were decreased in 6-month double-tg mice. Behavioral tests show impaired cognitive/memory performance of 9-month double-tg compared to Tg-SwDI mice as well as WT and Abcg2-KO mice. These results suggest that Abcg2 deficiency increases oxidative stress and alters inflammatory response in the brain and exacerbates cognitive/memory deficit in double-tg mice at different developmental stages.

Topics: Aging; Amyloid beta-Peptides; Animals; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Cognition Disorders; Cytokines; Disease Progression; DNA; Encephalitis; Enzyme-Linked Immunosorbent Assay; Glutathione; Heme Oxygenase-1; Immunohistochemistry; Intercellular Adhesion Molecule-1; Maze Learning; Mice; Mice, Knockout; Mice, Transgenic; NF-E2-Related Factor 2; Oxidative Stress; Peptide Fragments; Real-Time Polymerase Chain Reaction; Signal Transduction

Alzheimer's disease (AD) is the most common form of dementia. It is a progressive neurodegenerative disorder that leads to gradual loss of cognitive and functional abilities, and development of behavioral disturbances. Previous studies using Aβ(1-40) microinjection in animal models focused on cognitive deficits in spatial learning and avoidance conditioning. However, no attempt has been made to determine the sensitivity of an Aβ(1-40)-manipulated animal model in tasks involving reward-directed instrumental learning (RDIL). Thus, the present study was designed to investigate the effects of intra hippocampal microinjection of Aβ(1-40) on the acquisition and maintenance of a basic instrumental response (lever-pressing), then on the goal directed (higher response ratio) and habit (visual signal discrimination and extinction) learning, as well as on neurotransmitter changes which could potentially alter the regulatory processes involved in instrumental learning. Our present findings demonstrated that the focal hippocampal microinjection of Aβ(1-40) rendered rats unable to process new cue/contextual information in the formation of causal relation, rather than affecting the operant action itself. Although the injected Aβ(1-40) did not directly influence performance, it did prevent the information from being translated into action. Moreover, the neurotransmitter results indicated that multiple neural signaling might be involved in the regulation of RDIL in the Aβ(1-40) injection model. In conclusion, results suggested that our series of instrumental learning tasks may have potential in dementia research as a novel method for testing cognitive behavior.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Cognition Disorders; Conditioning, Operant; Discrimination, Psychological; Disease Models, Animal; Extinction, Psychological; Male; Neurotransmitter Agents; Peptide Fragments; Random Allocation; Rats; Rats, Wistar; Reaction Time; Reinforcement Schedule; Reward

Amyloid-beta peptides (Aβ) can trigger apoptotic cascades in neurons. We found previously that memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors approved for the treatment of moderate to severe Alzheimer's disease, can prevent neurodegeneration induced by intracranial Aβ(1-40) injection. In this study, we tested the hypothesis that memantine prevents Aβ(1-40)-mediated cognitive impairment, neurodegeneration, and apoptosis of hippocampal neurons in rats. In addition, we hypothesized that Aβ(1-40) injection would induce changes in the levels of one or more apoptosis-related proteins, and that these changes would be attenuated by memantine treatment. Female Sprague-Dawley rats were administered memantine (continuous subcutaneous application, 9.6-14.4mg/kg/day; n=8) or vehicle (water; n=8) for 9 days. Two days after treatment initiation, the animals were bilaterally injected with Aβ(1-40) into the CA1/DG region of the hippocampus, subjected to active avoidance testing for 7 days, and sacrificed for immunohistochemical examination of four caspases (3, 6, 8, and 9) and three proteins of the Bcl-2 family (Bcl-2, Bax, and Bad). Injection of Aβ resulted in neurodegeneration, DNA fragmentation, increased Bcl-2 immunostaining, and significantly impaired performance in an active avoidance task, all which were significantly attenuated in rats treated with memantine. No differences in immunoreactivity of caspases 3, 6, 8, and 9 were discovered between groups after 7 days. Additional experiments demonstrated that an increase in caspase 8 immunostaining, observed 3 days after Aβ(1-40) injection, was significantly attenuated in memantine-treated rats. These data suggest that, in rats, memantine can prevent amyloid-triggered expression of apoptosis-related markers and concomitant cognitive deficits.

Topics: Amyloid beta-Peptides; Animals; Apoptosis; Caspase 8; Cognition Disorders; Female; Hippocampus; Injections; Memantine; Memory; Neurons; Neuroprotective Agents; Peptide Fragments; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley

ATP-binding cassette transporter A1 (ABCA1) transporter regulates cholesterol efflux and is an essential mediator of high-density lipoprotein (HDL) formation. In amyloid precursor protein (APP) transgenic mice, Abca1 deficiency increased amyloid deposition in the brain paralleled by decreased levels of Apolipoprotein E (ApoE). The APOEε4 allele is the major genetic risk factor of sporadic Alzheimer's disease (AD). Here, we reveal the effect of Abca1 deficiency on phenotype in mice expressing human ApoE3 or ApoE4. We used APP/E3 and APP/E4 mice generated by crossing APP/PS1ΔE9 transgenic mice to human APOE3- and APOE4-targeted replacement mice and examined Abca1 gene dose effect on amyloid deposition and cognition. The results from two behavior tests demonstrate that lack of one copy of Abca1 significantly exacerbates memory deficits in APP/E4/Abca1(-/+) but not in APP/E3/Abca1(-/+) mice. The data for amyloid plaques and insoluble amyloid-β (Aβ) also show that Abca1 hemizygosity increases Aβ deposition only in APP/E4/Abca1(-/+) but not in APP/E3/Abca1(-/+) mice. Our in vivo microdialysis assays indicate that Abca1 deficiency significantly decreases Aβ clearance in ApoE4-expressing mice, while the effect of Abca1 on Aβ clearance in ApoE3-expressing mice was insignificant. In addition, we demonstrate that plasma HDL and Aβ42 levels in APP/E4/Abca1(-/+) mice are significantly decreased, and there is a negative correlation between plasma HDL and amyloid plaques in brain, suggesting that plasma lipoproteins may be involved in Aβ clearance. Overall, our results prove that the presence of functional Abca1 significantly influences the phenotype of APP mice expressing human ApoE4 and further substantiate therapeutic approaches in AD based on ABCA1-APOE regulatory axis.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Apolipoprotein E3; Apolipoprotein E4; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Brain; Cholesterol; Cognition Disorders; Conditioning, Psychological; Enzyme-Linked Immunosorbent Assay; Fear; Gene Expression Regulation; Humans; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microdialysis; Mutation; Peptide Fragments; Phenotype; Presenilin-1

The amyloid-β peptide Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, which is found just as frequently in the brains of affected individuals, remains unresolved. We generated knock-in mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygosity was embryonic lethal, indicating that the mutation involves a loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevated Aβ43, impairment of short-term memory and acceleration of amyloid-β pathology, which accompanied pronounced accumulation of Aβ43 in plaque cores similar in biochemical composition to those observed in the brains of affected individuals. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aβ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with the age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic and abundant in vivo.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Arginine; Cell Line, Tumor; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Embryo, Mammalian; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Humans; Immunoprecipitation; Isoleucine; L-Lactate Dehydrogenase; Male; Maze Learning; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Mutation; Neuroblastoma; Neurons; Peptide Fragments; Presenilin-1

The Arctic APP mutation (E693G) leads to dementia with clinical features similar to Alzheimer disease (AD), but little is known about the pathogenic mechanism of this mutation. To address this question, we have generated a transgenic mouse model, TgAPParc, with neuron-specific expression of human APP with the Arctic mutation (hAPParc). Heterozygous mice from two separate founder lines with different levels of expression of hAPParc were analyzed with respect to brain morphology and behavior every 3 months until the age of 18 months. Standard histological stainings and immunohistochemistry using a panel of Aβ antibodies showed an age- and dose-dependant progression of amyloid deposition in the brain, starting in the subiculum and spreading to the thalamus. Cognitive behavioral testing revealed deficits in hippocampus-dependent spatial learning and memory in the Barnes maze test. This study demonstrates that the Arctic APP mutation is sufficient to cause amyloid deposition and cognitive dysfunction, and thus the TgAPParc mouse model provides a valuable tool to study the effect of the Arctic mutation in vivo without possible confounding effect of other APP mutations.

Topics: Age Factors; Alanine; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cognition Disorders; Disease Progression; Enzyme-Linked Immunosorbent Assay; Escape Reaction; Exploratory Behavior; Glycine; Humans; Learning Disabilities; Maze Learning; Mice; Mice, Transgenic; Mutation; Peptide Fragments; Statistics, Nonparametric

Alzheimer's disease is a neurodegenerative disorder associated with abnormal accumulation of amyloid-β (Aβ) which can release endothelin (ET). The present study was conducted to investigate the effect of ET antagonists on Aβ-induced changes in ETA and ETB receptor expression, oxidative stress, and cognitive impairment. Male Sprague-Dawley rats were treated with Aβ1-40 in the lateral cerebral ventricles and were administered vehicle or ET antagonists for 14 days. Aβ treatment produced an increase in ETA receptor expression in the cerebral cortex, hippocampus, and brain stem by 72%, 85%, and 90%, respectively. No change in ETB receptor expression was observed. There was an increase in malondialdehyde (MDA) and decrease in reduced glutathione (GSH) and superoxide dismutase (SOD) levels in Aβ-treated rats. In the Morris swim task, Aβ treated rats showed a significant impairment in spatial memory. ET receptor antagonists, BQ123, BMS182874, and TAK-044, significantly decreased Aβ-induced increase in ETA expression in the cortex, hippocampus, and brain stem. Rats treated with ET antagonists showed significant attenuation of Aβ-induced changes in the brain MDA, GSH, and SOD levels. Rats treated with specific ETA receptor antagonists, BQ123 and BMS182874, significantly reduced the cognitive impairment induced by Aβ. However, nonspecific ETA/ETB receptor antagonist TAK-044 did not show any improvement in the learning and memory parameter. This study demonstrates that ETA receptor antagonists are effective in preventing cognitive impairment, changes in ETA expression and oxidative stress induced by Aβ. It is concluded that ETA receptor antagonists may be useful in improving cognitive impairment due to Alzheimer's disease.

Topics: Amyloid beta-Peptides; Animals; Cognition Disorders; Dansyl Compounds; Endothelin A Receptor Antagonists; Gene Expression Regulation; Male; Oxidative Stress; Peptide Fragments; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

At diagnosis, Alzheimer's disease (AD) brains are extensively burdened with plaques and tangles and display a degree of synaptic failure most likely beyond therapeutic treatment. It is therefore crucial to identify early pathological events in the progression of the disease. While it is not currently feasible to identify and study early, pre-clinical stages of AD, transgenic (Tg) models offer a valuable tool in this regard. Here we investigated cognitive, structural and biochemical CNS alterations occurring in our newly developed McGill-Thyl-APP Tg mice (over-expressing the human amyloid precursor protein with the Swedish and Indiana mutations) prior to extracellular plaque deposition. Pre-plaque, 3-month old Tg mice already displayed cognitive deficits concomitant with reorganization of cortical cholinergic pre-synaptic terminals. Conformational specific antibodies revealed the early appearance of intracellular amyloid β (Aβ)-oligomers and fibrillar oligomers in pyramidal neurons of cerebral cortex and hippocampus. At the same age, the cortical levels of insulin degrading enzyme -a well established Aβ-peptidase, were found to be significantly down-regulated. Our results suggest that, in the McGill-Thy1-APP Tg model, functional, structural and biochemical alterations are already present in the CNS at early, pre-plaque stages of the pathology. Accumulation of intraneuronal neurotoxic Aβ-oligomers (possibly caused by a failure in the clearance machinery) is likely to be the culprit of such early, pre-plaque pathology. Similar neuronal alterations might occur prior to clinical diagnosis in AD, during a yet undefined 'latent' stage. A better understanding of such pre-clinical AD might yield novel therapeutic targets and or diagnostic tools.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Cerebellum; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Drug Evaluation, Preclinical; Gene Expression Regulation; Hippocampus; Humans; Maze Learning; Mice; Mice, Transgenic; Mutation; Nuclear Receptor Subfamily 4, Group A, Member 2; Peptide Fragments; Phosphopyruvate Hydratase; Recognition, Psychology; Vesicular Acetylcholine Transport Proteins

Physical exercise is considered to exert a positive neurophysiological effect that helps to maintain normal brain activity in the elderly. Expectations that it could help to fight Alzheimer's disease (AD) were recently raised. This study analyzed the effects of different patterns of physical exercise on the 3xTg-AD mouse. Male and female 3xTg-AD mice at an early pathological stage (4-month-old) have had free access to a running wheel for 1 month, whereas mice at a moderate pathological stage(7-month-old) have had access either during 1 or 6 months. The non-transgenic mouse strain was used as a control. Parallel animal groups were housed in conventional conditions. Cognitive loss and behavioral and psychological symptoms of dementia (BPSD)-like behaviors were present in the 3xTg-AD mice along with alteration in synaptic function and ong-term potentiation impairment in vivo. Brain tissue showed AD-pathology and oxidative-related changes. Disturbances were more severe at the older age tested. Oxidative stress was higher in males but other changes were similar or higher in females. Exercise treatment ameliorated cognitive deterioration and BPSD-like behaviors such as anxiety and the startle response. Synaptic changes were partially protected by exercise. Oxidative stress was reduced. The best neuroprotection was generally obtained after 6 months of exercise in 7-month-old 3xTg-AD mice. Improved sensorimotor function and brain tissue antioxidant defence were induced in both 3xTg-AD and NonTg mice. Therefore, the benefits of aerobic physical exercise on synapse, redox homeostasis, and general brain function demonstrated in the 3xTg-AD mouse further support the value of this healthy life-style against neurodegeneration.

Topics: Acoustic Stimulation; Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Body Weight; Brain; Cognition Disorders; Conditioning, Operant; Dark Adaptation; Disease Models, Animal; Electroencephalography; Enzyme-Linked Immunosorbent Assay; Excitatory Postsynaptic Potentials; Exercise; Exploratory Behavior; Female; Glutathione; Glutathione Disulfide; Humans; Male; Maze Learning; Mice; Mice, Transgenic; Mutation; Neural Inhibition; Peptide Fragments; Physical Therapy Modalities; Presenilin-1; Reflex, Startle; tau Proteins

Retrospective and prospective epidemiologic studies suggest that enhanced coffee/caffeine intake during aging reduces risk of Alzheimer's disease (AD). Underscoring this premise, our studies in AD transgenic mice show that long-term caffeine administration protects against cognitive impairment and reduces brain amyloid-β levels/deposition through suppression of both β- and γ-secretase. Because coffee contains many constituents in addition to caffeine that may provide cognitive benefits against AD, we examined effects of caffeinated and decaffeinated coffee on plasma cytokines, comparing their effects to caffeine alone. In both AβPPsw+PS1 transgenic mice and non-transgenic littermates, acute i.p. treatment with caffeinated coffee greatly and specifically increased plasma levels of granulocyte-colony stimulating factor (GCSF), IL-10, and IL-6. Neither caffeine solution alone (which provided high plasma caffeine levels) or decaffeinated coffee provided this effect, indicating that caffeine synergized with some as yet unidentified component of coffee to selectively elevate these three plasma cytokines. The increase in GCSF is particularly important because long-term treatment with coffee (but not decaffeinated coffee) enhanced working memory in a fashion that was associated only with increased plasma GCSF levels among all cytokines. Since we have previously reported that long-term GCSF treatment enhances cognitive performance in AD mice through three possible mechanisms (e.g., recruitment of microglia from bone marrow, synaptogenesis, and neurogenesis), the same mechanisms could be complimentary to caffeine's established ability to suppress Aβ production. We conclude that coffee may be the best source of caffeine to protect against AD because of a component in coffee that synergizes with caffeine to enhance plasma GCSF levels, resulting in multiple therapeutic actions against AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Caffeine; Coffee; Cognition Disorders; Cytokines; Disease Models, Animal; Granulocyte Colony-Stimulating Factor; Humans; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neuropsychological Tests; Peptide Fragments; Phosphodiesterase Inhibitors; Presenilin-1; Theophylline; Time Factors

Amyloid-β peptide (Aβ) plays an important role in the pathogenesis of Alzheimer's disease (AD). Aβ is generated by proteolysis of β-amyloid precursor protein (APP) and is cleared by enzyme-mediated degradation and phagocytosis by microglia and astrocytes. Some cytokines, such as TGF-β1, stimulate this phagocytosis. In contrast, cellular upregulation of HSP70 expression provides cytoprotection against Aβ. HSP70 activity in relation to inhibition of Aβ oligomerization and stimulation of Aβ phagocytosis has also been reported. Although these in vitro results suggest that stimulating the expression of HSP70 could prove effective in the treatment of AD, there is a lack of in vivo evidence supporting this notion. In this study, we address this issue, using transgenic mice expressing HSP70 and/or a mutant form of APP (APPsw). Transgenic mice expressing APPsw showed less of an apparent cognitive deficit when they were crossed with transgenic mice expressing HSP70. Transgenic mice expressing HSP70 also displayed lower levels of Aβ, Aβ plaque deposition, and neuronal and synaptic loss than control mice. Immunoblotting experiments and direct measurement of β- and γ-secretase activity suggested that overexpression of HSP70 does not affect the production Aβ. In contrast, HSP70 overexpression did lead to upregulation of the expression of Aβ-degrading enzyme and TGF-β1 both in vivo and in vitro. These results suggest that overexpression of HSP70 in mice suppresses not only the pathological but also the functional phenotypes of AD. This study provides the first in vivo evidence confirming the potential therapeutic benefit of HSP70 for the prevention or treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Brain; Cells, Cultured; Cognition Disorders; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; HSP70 Heat-Shock Proteins; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Peptide Fragments; Phenotype

Autopsy evidence suggests that the presence of both Alzheimer(')s disease (AD) and cerebral infarction pathology is associated with more severe cognitive impairment than that produced by AD pathology alone. This study aims to investigate the effect of cerebral ischemia on cognitive function in rats with AD constructed by hippocampal injection and to determine its underlying mechanism, which is proposed to be of significance to the treatment of AD.. AD was modeled by injection of aggregated Aβ(1-40), either alone or followed by hippocampal endothelin-1 injection to mimic cerebral ischemia in hippocampus, into the right dentate gyrus (DG) of rats. The Morris water maze was used to evaluate cognitive function. Aβ deposition, neuronal loss and phosphorylated tau expression in hippocampus were examined by Congo red staining, Nissl's staining and immunohistochemistry, respectively. Reactive astrocytes, IL-1β and TNF-α expressions were measured by immunohistochemistry, in situ hybridization and reverse transcription-polymerase chain reaction.. Compared with rats treated with either Aβ or endothelin alone, rats treated with both Aβ and endothelin showed more aggravated cognitive impairment and more Aβ deposits, neuron loss, phosphorylated tau expression, reactive astrocytes, IL-1β and TNF-α expressions in hippocampus.. Hippocampal ischemia aggravates cognitive impairment of AD rats by increasing Aβ deposits, neuron loss and tau phosphorylation in hippocampus. The enhanced inflammatory response may be responsible for cerebral ischemia-induced aggravation of cognitive impairment in AD rats. Based on these findings, prevention and treatment of cerebral ischemia may improve clinical symptoms of AD and suppress the progression of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Brain Ischemia; Cognition Disorders; Disease Models, Animal; Drug Therapy, Combination; Endothelin-1; Hippocampus; Interleukin-1beta; Male; Maze Learning; Memory; Neurons; NF-kappa B; Peptide Fragments; Phosphorylation; Rats; Rats, Sprague-Dawley; tau Proteins; Tumor Necrosis Factor-alpha

The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aβ42) to that of the major reaction product (Aβ40). Although no PS1 mutations are present, altered Aβ42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Aβ42 as amyloid.. Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP α-secretases and γ-secretases, yielding a fragment that we have named p3-Alc(α) because of the parallel genesis of p3-Alc(α) peptides and the p3 fragment of APP. As with Aβ, both major and minor p3-Alc(α) s are generated. We studied the alternative processing of p3-Alc(α) in various clinical populations.. We previously reported that changes in the Aβ42/40 ratio showed covariance in a linear relationship with the levels of p3-Alc(α) [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alc(α) in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alc(α) variant, p3-Alc(α) 38, was elevated (p < 0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts.. These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Cognition Disorders; Female; Humans; Immunoprecipitation; Male; Peptide Fragments; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry

To evaluate the relations between PET Pittsburgh compound B (PiB-PET) binding (amyloid imaging) and plasma Aβ in patients with mild cognitive impairment (MCI) and similarly aged controls.. In 20 patients with MCI and 19 cognitively intact controls (case-control study), PiB binding potential (BP(nd)) was assessed in 4 regions, and total brain excluding cerebellum, referenced to cerebellar binding. The mean of plasma Aβ levels measured in duplicate was analyzed.. Plasma Aβ42/Aβ40 ratio was decreased in MCI compared to controls (mean 0.15 SD 0.04 vs mean 0.19 SD 0.07, p = 0.03) but Aβ40 (p = 0.3) and Aβ42 (p = 0.06) levels did not differ between the 2 groups. PiB BP(nd) was increased in MCI compared to controls in the cingulate (p = 0.02), parietal (p = 0.02), and total brain (p = 0.03), but not in prefrontal cortex (p = 0.08) or parahippocampal gyrus (p = 0.07). Linear regression analyses adjusting for age, sex, and cognitive test scores showed that low Aβ42/Aβ40 ratio was associated with high cingulate, parietal, and total brain PiB binding (0.01< p ≤ 0.05). These associations between PiB binding and the Aβ42/Aβ40 ratio were strongest in PiB-positive subjects and within the MCI group.. Though cross-sectional, the findings support the "sink" hypothesis that increased brain Aβ is accompanied by lower peripheral levels of Aβ, particularly the Aβ42/Aβ40 ratio in patients with MCI. The association between PiB binding and the plasma Aβ42/Aβ40 ratio suggests possible use of plasma Aβ combined with PiB binding as a risk biomarker with potential clinical application.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Case-Control Studies; Cognition Disorders; Female; Humans; Linear Models; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Peptide Fragments; Positron-Emission Tomography; Retrospective Studies; Thiazoles

The cholinesterase inhibitor, rivastigmine, ameliorates cognitive dysfunction and is approved for the treatment of Alzheimer's disease (AD). Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); however, the impact of BuChE inhibition on cognitive dysfunction remains to be determined. We compared the effects of a selective BuChE inhibitor, N1-phenethyl-norcymserine (PEC), rivastigmine and donepezil (an AChE-selective inhibitor) on cognitive dysfunction induced by amyloid-β peptide (Aβ(1-40)) in mice. Five-week-old imprinting control region (ICR) mice were injected intracerebroventricularly (i.c.v.) with either Aβ(1-40) or the control peptide Aβ(40-1) on Day 0, and their recognition memory was analyzed by a novel object recognition test. Treatment with donepezil (1.0mg/kg), rivastigmine (0.03, 0.1, 0.3mg/kg) or PEC (1.0, 3.0mg/kg) 20min prior to, or immediately after the acquisition session (Day 4) ameliorated the Aβ(1-40) induced memory impairment, indicating a beneficial effect on memory acquisition and consolidation. In contrast, none of the investigated drugs proved effective when administrated before the retention session (Day 5). Repeated daily administration of donepezil, rivastigmine or PEC, on Days 0-3 inclusively, ameliorated the cognitive dysfunction in Aβ(1-40) challenged mice. Consistent with the reversal of memory impairments, donepezil, rivastigmine or PEC treatment significantly reduced Aβ(1-40) induced tyrosine nitration of hippocampal proteins, a marker of oxidative damage. These results indicate that BuChE inhibition, as well as AChE inhibition, is a viable therapeutic strategy for cognitive dysfunction in AD.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Cognition Disorders; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Indans; Male; Mice; Mice, Inbred ICR; Motor Activity; Peptide Fragments; Phenylcarbamates; Piperidines; Recognition, Psychology; Rivastigmine

Transactive response DNA binding protein 43 (TDP-43) plays a central role in the neuropathology of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, but the relationship between TDP-43 abnormalities and Alzheimer disease (AD) remains unclear. To determine whether TDP-43 can serve as a neuropathologic marker of AD, we performed biochemical characterization and quantification of TDP-43 in homogenates from parietal neocortex of subjects with aclinical diagnosis of no cognitive impairment (NCI, n = 12), mild cognitive impairment (MCI, n = 12), or AD (n = 12). Immunoblots revealed increased detergent-insoluble TDP-43 in the cortex of 0, 3, and 6 of the 12 individuals with NCI, MCI, or AD, respectively. Detergent-insoluble TDP-43 was positively correlated with the accumulation of soluble Aβ42, amyloid plaques, and paired helical filamenttau. In contrast, phospho-TDP-43 was decreased in the cytosolic fraction and detergent-soluble membrane/nuclear fraction from AD patients and correlated with antemortem cognitive function.Immunofluorescence analysis confirmed that the frequencies of individuals with TDP-43 or phospho-TDP-43 cytoplasmic inclusions were higher in AD than in NCI, with MCI at an intermediate level. These data indicate that abnormalities of TDP-43 occur in an important subset of MCI and AD patients and that they correlate with the clinical and neuropathologic features of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Brain; Cognition Disorders; DNA-Binding Proteins; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Mental Status Schedule; Peptide Fragments; Postmortem Changes

Alzheimer's disease (AD) is a neurodegenerative disorder leading to a progressive loss of cognitive function and is pathologically characterized by senile plaques and neurofibrillary tangles. Glycogen synthase kinase-3 (GSK-3) is involved in AD pathogenesis. GSK-3 is reported not only to phosphorylate tau, a major component of neurofibrillary tangles, but also to regulate the production of amyloid β, which is deposited in senile plaques. Therefore, pharmacological inhibition of GSK-3 is considered an attractive therapeutic approach. In this study, we report the pharmacological effects of a novel GSK-3 inhibitor, 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole (MMBO), which displays high selectivity for GSK-3 and brain penetration following oral administration. MMBO inhibited tau phosphorylation in primary neural cell culture and also in normal mouse brain. When administered to a transgenic mouse model of AD, MMBO significantly decreased hippocampal tau phosphorylation at GSK-3 sites. Additionally, chronic MMBO administration suppressed tau pathology as assessed by AT8-immunoreactivity without affecting amyloid β pathology. Finally, in behavioral assessments, MMBO significantly improved memory and cognitive deficits in the Y-maze and in novel object recognition tests in the transgenic AD mouse model. These results indicate that pharmacological GSK-3 inhibition ameliorates behavioral dysfunction with suppression of tau phosphorylation in an AD mouse model, and that MMBO might be beneficial for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Benzofurans; Brain; Cell Culture Techniques; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Exploratory Behavior; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Maze Learning; Mice; Mice, Transgenic; Mutation; Neurons; Oxadiazoles; Peptide Fragments; Phosphorylation; Presenilin-1; tau Proteins; Time Factors

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Cognition Disorders; Cross-Sectional Studies; Disease Progression; Early Diagnosis; Female; Humans; Male; Middle Aged; Peptide Fragments; Predictive Value of Tests; Severity of Illness Index

Alzheimer's disease (AD), a chronic degenerative and inflammatory brain disorder characterized by neuronal dysfunction and loss, is linked to accumulation of beta-amyloid (Abeta) peptide. Tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) are proteins that have key roles in immune cell activation, inflammation and cognitive function in the brain. Here, we evaluated the link between TNF-alpha and COX-2 on the acute responses elicited by Abeta. Behavioral and molecular analyses were performed in mice after an intracerebroventricular (i.c.v.) injection of Abeta(1-40). Genetic and/or pharmacological approaches were used to inhibit TNF-alpha and COX-2. I.c.v. Abeta(1-40) injection in mice activates TNF-alpha signaling pathway resulting in COX-2 upregulation, synaptic loss and cognitive decline. Pharmacological studies revealed that COX-2 is involved in the cognitive impairment mediated by TNF-alpha. However, COX-2 inhibition failed in reducing the synaptophysin loss induced by Abeta(1-40). The COX-2 upregulation induced by Abeta(1-40) was attributed to activation of different protein kinases and transcriptional factors that are greatly regulated by TNF-alpha. Together, these results indicate that Abeta(1-40) induces the activation of several TNF-alpha-dependent intracellular signaling pathways that play a key role in the control of COX-2 upregulation and activation, synaptic loss and cognitive decline in mice. Therefore, selective TNF-alpha inhibitors may be potentially interesting tools for AD drug development.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Antibodies; Cognition Disorders; CREB-Binding Protein; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Electrophoretic Mobility Shift Assay; Enzyme Inhibitors; Hippocampus; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitrobenzenes; Peptide Fragments; Protein Kinase C; Receptors, Tumor Necrosis Factor, Type I; Recognition, Psychology; Signal Transduction; Sulfonamides; Tumor Necrosis Factor-alpha; Up-Regulation

Early Alzheimer's disease (AD) is marked by cholinergic hypofunction, neuronal marker loss, and decreased nicotinic acetylcholine receptor (nAChR) density from the cortex and hippocampus. alpha7 nAChRs expressed on cholinergic projection neurons and target regions have been implicated in neuroprotection against beta-amyloid (Abeta) toxicity and maintenance of the septohippocampal phenotype. We tested the role that alpha7 nAChRs perform in the etiology of early AD by genetically deleting the alpha7 nAChR subunit from the Tg2576 mouse model for AD and assessing animals for cognitive function and septohippocampal integrity. Thus, Tg2576 mice transgenic for mutant human amyloid precursor protein (APP) were crossed with alpha7 nAChR knock-out mice (A7KO) to render an animal with elevated Abeta in the absence of alpha7 nAChRs (A7KO-APP). We found that learning and memory deficits seen in 5-month-old APP mice are more severe in the A7KO-APP animals. Analyses of animals in early-stage preplaque cognitive decline revealed signs of neurodegeneration in A7KO-APP hippocampus as well as loss of cholinergic functionality in the basal forebrain and hippocampus. These changes occurred concomitant with the appearance of a dodecameric oligomer of Abeta that was absent from all other genotypic groups, generating the hypothesis that increased soluble oligomeric Abeta may underlie additional impairment of A7KO-APP cognitive function. Thus, alpha7 nAChRs in a mouse model for early-stage AD appear to serve a neuroprotective role through maintenance of the septohippocampal cholinergic phenotype and preservation of hippocampal integrity possibly through influences on Abeta accumulation and oligomerization.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Behavior, Animal; Cell Count; Choline O-Acetyltransferase; Cognition Disorders; Conditioning, Classical; Disease Models, Animal; Exploratory Behavior; Fear; Hippocampus; Immunoprecipitation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neural Pathways; Neurons; NFI Transcription Factors; Pattern Recognition, Visual; Peptide Fragments; Receptors, Nicotinic; Retention, Psychology; Septum of Brain; Time Factors

Several studies have shown that reduced amyloid-beta 1-42 (Abeta(42)) and increased tau levels in cerebrospinal fluid (CSF) reflect increased Alzheimer's disease (AD) pathology in the brain. beta-site APP cleaving enzyme (BACE1) is thought to be the major beta-secretase involved in Abeta production in the brain, and therefore we investigated the relation between BACE1 activity and CSF markers Abeta(40), Abeta(42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau) in CSF of control (n=12), mild cognitive impairment (n=18), and AD (n=17) subjects. Patients were classified according to their Abeta(42), t-tau, and p-tau CSF biomarker levels, with either an AD-like biomarker profile (two or three biomarkers abnormal: Abeta(42) < 495 pg/ml in combination with t-tau > 356 pg/ml, and/or p-tau > 54 pg/ml) or a normal biomarker profile (

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Apolipoproteins E; Aspartic Acid Endopeptidases; Cognition Disorders; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Peptide Fragments; Statistics as Topic; tau Proteins

To determine if plasma β-amyloid (Aβ) levels (1) can be linked to specific cognitive changes that constitute conversion to Alzheimer disease (AD) and (2) correspond to cognitive change independent of dementia.. Longitudinal study including 3 visits during approximately 4¹/₂ years (2000-2006).. Northern Manhattan community.. Eight hundred eighty individuals from a population-based and ethnically diverse sample who had 2 plasma Aβ measurements and were dementia free at the time of the first Aβ sample; 481 remained cognitively healthy, 329 were cognitively or functionally impaired but not demented at any point, and 70 developed AD.. General estimating equations tested the association between plasma Aβ (baseline and change in values) and cognitive change (composite score and memory, language, and visuospatial indices).. High baseline plasma Aβ42 (P = .01) and Aβ40 (P = .01) and decreasing/relatively stable Aβ42 (P = .01) values were associated with faster decline in multiple cognitive domains. In those who remained cognitively healthy, high baseline plasma Aβ42 (P = .01) and decreasing/relatively stable plasma Aβ42 (P = .01) was associated with faster cognitive decline, primarily in memory.. The association between plasma Aβ and multiple aspects of cognition more clearly specifies the previously documented downward trajectory of plasma Aβ with AD onset. The predominant association with memory seen only in healthy elderly individuals also suggests that plasma Aβ is linked with even earlier neurologic changes that may or may not culminate in dementia.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Apolipoproteins E; Cognition Disorders; Community Health Planning; Enzyme-Linked Immunosorbent Assay; Female; Genotype; Humans; Longitudinal Studies; Male; Peptide Fragments

Numerous studies have shown a marked decrease of beta-amyloid(42) (Abeta(42)) in the cerebrospinal fluid (CSF) of patients with incipient Alzheimer's disease (AD). However, studies on Abeta in plasma are contradictory, and show very marginal differences between patients and controls. Here, we analyzed plasma samples using a new multiplex immunoassay for simultaneous analysis of Abeta(1-40), Abeta(n-40), Abeta(1-42), and Abeta(n-42). The plasma samples were obtained at baseline from two independent cohorts of patients with mild cognitive impairment (MCI) and age-matched controls. In the first cohort, 41% of the 117 MCI cases converted to AD during a clinical follow-up period of 4-7 years. In the second cohort, 14% of the 110 MCI subjects developed AD during a clinical follow-up period of 2-4 years. None of the plasma Abeta isoforms differed between MCI patients that subsequently developed AD and healthy controls or stable MCI patients. The Cox proportional hazards model did not reveal any differences in the probability of progression from MCI to AD related to plasma Abeta levels. In contrast, low levels of Abeta(1-42) in CSF were strongly associated with increased risk of future AD. The absence of a change in plasma Abeta in incipient AD, despite the marked change in CSF, may be explained by the lack of a correlation between the levels of Abeta(1-42) in CSF and plasma. In conclusion, the results show that CSF biomarkers are better predictors of progression to AD than plasma Abeta isoforms.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognition Disorders; Cohort Studies; Disease Progression; Eating; Female; Follow-Up Studies; Humans; Male; Middle Aged; Peptide Fragments; Proportional Hazards Models; Risk Factors; Time Factors

Alzheimer's disease (AD) is a degenerative disorder that leads to progressive cognitive decline. Alzheimer's disease develops as a result of over-production and aggregation of beta-amyloid (Abeta) peptides in the brain. The reason for variation in the gravity of symptoms among AD patients is unknown and might result from patient-related factors including lifestyle. Individuals suffering from chronic stress are at an increased risk for developing AD. This study investigated the effect of chronic psychosocial stress in Abeta rat model of AD.. Psychosocial stress was induced with a rat intruder model. The rat model of AD was induced by 14-day osmotic pump infusion of a mixture of 300 pmol/day Abeta(1-40)/Abeta(1-42). The effect of chronic stress on the severity of Abeta-induced spatial learning and memory impairment was tested by three approaches: behavioral testing in the radial arm water maze, in vivo electrophysiological recording in anesthetized rat, and immunoblot analysis to determine protein levels of learning- and memory-related molecules.. A marked impairment of learning and memory developed when stress was combined with Abeta, more so than that caused by Abeta alone. Additionally, there was a significantly greater impairment of early-phase long-term potentiation (E-LTP) in chronically stressed/Abeta-treated rats than in either the stressed or Abeta-treated rats. This might be a manifestation of the reduction in protein levels of calcium/calmodulin-dependent protein kinase II (CaMKII) and the abnormal increase in calcineurin levels.. Chronic stress significantly intensified Abeta-induced deficits of short-term memory and E-LTP by a mechanism involving decreased CaMKII activation along with increased calcineurin levels.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Behavior, Animal; Biophysics; Calcineurin; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cognition Disorders; Disease Models, Animal; Down-Regulation; Electric Stimulation; Excitatory Postsynaptic Potentials; Hippocampus; Long-Term Potentiation; Male; Maze Learning; Patch-Clamp Techniques; Peptide Fragments; Rats; Rats, Wistar; Stress, Psychological

Evidence suggests a relationship between peripheral Abeta and AD. We hypothesized that higher levels of serum Abeta(1-42) would be associated with memory impairment, thought to occur early in the disease, and rises in serum Abeta(1-40), which occur later, would be associated with impairment in non-memory measures.. Using a cross-sectional design, we examined the relationship of serum Abeta(1-40), Abeta(1-42), and the ratio of Abeta(1-42/1-40) to neuropsychological measures in 40 cognitively normal controls, 13 MCI subjects, and 25 AD patients.. Serum Abeta(1-42) and the ratio of Abeta(1-42/1-40) were significantly higher in the MCI group compared to the controls. A significant relationship in the hypothesized direction (poorer scores associated with higher Abeta(1-40) serum levels) was found between Abeta(1-40) and measures of executive functions across the entire cohort of individuals tested and with measures of language and processing speed in the AD group. Regression analysis found that neuropsychological measures accounted for 26% of the variance in serum Abeta(1-40,) in the MCI/AD but not the controls. Furthermore that language and executive measures were significant predictors.. Results provide preliminary data to partially support our hypotheses and suggest that changes in serum Abeta levels may be attributed to pathological changes within the brain.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Cognition Disorders; Enzyme-Linked Immunosorbent Assay; Female; Humans; Language; Male; Memory Disorders; Neuropsychological Tests; Peptide Fragments; Regression Analysis

Chronic cerebral hypoperfusion (CCH) increases the risk of Alzheimer disease (AD) through several biologically plausible pathways, but the relationship between CCH and the development of AD remains uncertain. To investigate expression of APP, BACE1 and A beta in the hippocampus of BCCAO rats and study pathophysiological mechanism of AD from CCH. CCH rat model was established by chronic bilateral common carotid artery occlusion (BCCAO). Behavior was evaluated after BCCAO with Morris water maze and open-field task. Expression of A beta was measured by enzyme linked immunosorbent assay (ELISA). beta-Amyloid precursor protein cleavage enzyme 1 (BACE1) and beta-amyloid precursor protein (APP) were tested by ELISA, Western blotting and RT-PCR. Cognitive impairment occurred with CCH by Morris water maze test and open-field task. The BACE1 and A beta level in BCCAO rats was more increased than sham-operation control rats (P < 0.01) but APP had no difference(P > 0.05). The expression of BACE1 and A beta has no inter-group difference in BCCAO rats (P > 0.05). The level of BACE1 and A beta had positive correlation with cognitive impairment (P < 0.01) while no correlation was observed between APP and cognitive impairment. Chronic cerebral ischemia contributes to cognitive impairment and vascular pathogenesis of Alzheimer's disease that chronic cerebral hypoperfusion increases BACE1 and A beta level in brain.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Behavior, Animal; Blotting, Western; Brain Ischemia; Cognition Disorders; Enzyme-Linked Immunosorbent Assay; Escape Reaction; Maze Learning; Peptide Fragments; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation

Chromatin modification through histone acetylation is a molecular pathway involved in the regulation of transcription underlying memory storage. Sodium 4-phenylbutyrate (4-PBA) is a well-known histone deacetylase inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. In this study, we report that administration of 4-PBA reversed spatial learning and memory deficits in an established mouse model of Alzheimer's disease (AD) without altering beta-amyloid burden. We also observed that the phosphorylated form of tau was decreased in the AD mouse brain after 4-PBA treatment, an effect probably due to an increase in the inactive form of the glycogen synthase kinase 3beta (GSK3beta). Interestingly, we found a dramatic decrease in brain histone acetylation in the transgenic mice that may reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA restored brain histone acetylation levels and, as a most likely consequence, activated the transcription of synaptic plasticity markers such as the GluR1 subunit of the AMPA receptor, PSD95, and microtubule-associated protein-2. The results suggest that 4-PBA, a drug already approved for clinical use, may provide a novel approach for the treatment of AD.

Topics: Acetylation; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Cells, Cultured; Chromatin Immunoprecipitation; Cognition Disorders; Disease Models, Animal; Embryo, Mammalian; Hippocampus; Histones; Humans; Maze Learning; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Peptide Fragments; Phenylbutyrates; Tauopathies

Little is known of combined utility of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers for prediction of Alzheimer's disease (AD) and longitudinal data is scarce. We examined these biomarkers at baseline and longitudinally in incipient AD. Forty-five subjects [21 controls (NL-NL), 16 stable MCI (MCI-MCI), 8 MCI who declined to AD (MCI-AD)] received MRI and lumbar puncture at baseline and after 2 years. CSF measures included total and phosphorylated tau (T-tau, P-tau(231)), amyloid-beta (Abeta(42)/Abeta(40)) and isoprostane. Voxel-based morphometry identified gray matter concentration (GMC) differences best distinguishing study groups and individual GMC values were calculated. Rate of medial temporal lobe (MTL) atrophy was examined using regional boundary shift (rBS) method. At baseline, for MRI, MCI-AD showed reduced GMC-MTL, and for CSF higher CSF T-tau, P-tau(231), IP and lower Abeta(42)/Abeta(40) as compared with MCI-MCI or NL-NL. Longitudinally, rBS-MTL atrophy was higher in MCI-AD than in either MCI-MCI or NL-NL, particularly in the left hemisphere. CSF data showed longitudinally greater increases of isoprostane in MCI-AD as compared with NL-NL. Combining baseline CSF-P-tau(231) and GMC-MTL significantly increased overall prediction of AD from 74% to 84% (p(step)<0.05). These results provide support for including multiple modalities of biomarkers in the identification of memory clinic patients at increased risk for dementia.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Area Under Curve; Cognition Disorders; Female; Functional Laterality; Gas Chromatography-Mass Spectrometry; Humans; Image Processing, Computer-Assisted; Isoprostanes; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Peptide Fragments; Sensitivity and Specificity; tau Proteins

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Atrophy; Biomarkers; Brain; Cholinesterase Inhibitors; Cognition Disorders; Cross-Sectional Studies; Diagnostic Imaging; Disease Progression; Excitatory Amino Acid Antagonists; Humans; Memantine; Middle Aged; Neuropsychological Tests; Peptide Fragments; Population Dynamics; Risk Factors

Valid animal models for a specific human disease are indispensable for development of new therapeutic agents. The conclusions drawn from animal models largely depend on the validity of the model. Several studies have shown that administration of Abeta into the brain causes some of the pathological events observed in Alzheimer disease (AD). However, the validity of these models has not fully been examined. In this present study, we further characterized and validated Abeta1-40 injected mice as an animal model for AD, based on three major criteria: face, construct and predictive validity. Intracerebroventricular (i.c.v.) injection of Abeta1-40 into mice significantly impaired memory acquisition, but not memory retrieval, which implies similarity to the episodic anterograde memory deficit observed in the early stage of AD. Electrophysiological assessment showed that i.c.v. administration of Abeta1-40 significantly attenuated hippocampal long-term potentiation. Treatment with galantamine, a drug currently in clinical use for AD, significantly improved cognitive dysfunction in this model. These results demonstrate that i.c.v. injection of Abeta1-40 caused specific dysfunction of memory processes, which at least partly fulfills three validity criteria for AD. Symptomatic and pathophysiological similarities of this model to AD are quite important in considering the usefulness of this animal model. This validated animal model could be useful to develop and evaluate potential new drugs for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Ventricles; Cognition Disorders; Disease Models, Animal; Galantamine; Hippocampus; Injections, Intraventricular; Long-Term Potentiation; Male; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Neurotoxins; Nootropic Agents; Peptide Fragments

Amnestic mild cognitive impairment (aMCI) is considered a prodromal stage of Alzheimer's disease (AD). We measured plasma levels of amyloid-beta40 (Abeta40) and Abeta42 in 191 subjects with aMCI. Seventy-nine of them were clinically followed for two years. In the total cohort of aMCI cases, the average level of Abeta42, as well as the Abeta42/Abeta40 ratio, was significantly higher than those of the 102 cognitively normal age-matched subjects. The aMCI cases that converted to probable AD within 2 years had higher levels of Abeta42 and, to a lesser extent, Abeta40 than the stable cases. However the large variability of measured values indicates that plasma Abeta is not a suitable marker of incipient AD.

Topics: Aged; Amnesia; Amyloid beta-Peptides; Cognition Disorders; Cohort Studies; Disease Progression; Female; Humans; Male; Mental Status Schedule; Neuropsychological Tests; Peptide Fragments; Statistics, Nonparametric

The hallmarks of Alzheimer's disease include the deposition of beta-amyloid (Abeta), neuroinflammation, and cognitive deficits. The accumulation of activated glial cells in cognitive-related areas is critical for these alterations, although little is known about the mechanisms driving this event. Herein we used macrophage inflammatory protein-1alpha (MIP-1alpha(-/-))- or CC-chemokine receptor 5 (CCR5(-/-))-deficient mice to address the role played by chemokines in molecular and behavioral alterations induced by Abeta(1-40). Abeta(1-40) induced a time-dependent increase of MIP-1alpha mRNA followed by accumulation of activated glial cells in the hippocampus of wild-type mice. MIP-1alpha(-/-) and CCR5(-/-) mice displayed reduced astrocytosis and microgliosis in the hippocampus after Abeta(1-40) administration that was associated with decreased expression of cyclooxygenase-2 and inducible nitric oxide synthase, as well as reduced activation of nuclear factor-kappaB, activator protein-1 and cyclic AMP response element-binding protein. Furthermore, MIP-1alpha(-/-) and CCR5(-/-) macrophages showed impaired chemotaxis in vitro, although cytokine production in response to Abeta(1-40) was unaffected. Notably, the cognitive deficits and synaptic dysfunction induced by Abeta(1-40) were also attenuated in MIP-1alpha(-/-) and CCR5(-/-) mice. Collectively, these results indicate that the MIP-1alpha/CCR5 signaling pathway is critical for the accumulation of activated glial cells in the hippocampus and, therefore, for the inflammation and cognitive failure induced by Abeta(1-40). Our data suggest MIP-1alpha and CCR5 as potential therapeutic targets for Alzheimer's disease treatment.

Topics: Amyloid beta-Peptides; Animals; Cell Movement; Chemokine CCL3; Cognition Disorders; Cyclooxygenase 2; Gene Deletion; Hippocampus; Humans; Inflammation; Male; Memory; Mice; Mice, Inbred C57BL; Nervous System; Neuroglia; Nitric Oxide Synthase Type II; Peptide Fragments; Receptors, CCR5; Signal Transduction; Synapses; Transcription Factors; Up-Regulation

Alzheimer's disease is the most common form of dementia. Amyloid-beta protein is considered as a key factor of pathogenesis of Alzheimer's disease. l-3-n-butylphthalide (L-NBP), an anti-cerebral ischemia drug, has been shown to have therapeutic effects in vascular dementia animal models. In the present study, we investigated the potential of L-NBP to protect against cognitive impairment, oxidative damage and neuropathological changes induced by intracerebroventricular infusion of amyloid-beta peptide in rats. Daily treatments of 10 and 30 mg/kg L-NBP significantly improved spatial learning deficits and attenuated working memory deficits in Morris water maze task. L-NBP partially reversed the reduction of glutathione peroxidase activities and decreased malondialdehyde levels in the cortex and hippocampus. Furthermore, L-NBP markedly inhibited amyloid-beta-induced neuronal apoptosis, possibly by blocking caspase-3 activation. In addition, L-NBP reduced activation of glycogen synthase kinase-3beta and tau protein phosphorylation. Our results demonstrate that L-NBP protects against amyloid-beta-induced neurodegeneration and cognitive decline in a rat model, suggesting that it may have potential as a therapy for Alzheimer's disease.

Topics: Amyloid beta-Peptides; Animals; Apoptosis; Benzofurans; Cerebral Ventricles; Cognition Disorders; Infusion Pumps; Learning; Male; Memory; Neurons; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Phosphorylation; Rats; Rats, Wistar; tau Proteins

Recent studies suggest that vascular risk factors play a considerable role in the development of Alzheimer disease. Furthermore, the use of antihypertensive drugs has been suggested to reduce the incidence of dementia, including Alzheimer disease. In this study, we examined the effects of an angiotensin receptor blocker, olmesartan, on beta-amyloid-induced cerebrovascular dysfunction and cognitive impairment. Oral administration of a low dose of olmesartan attenuated cerebrovascular dysfunction in young Alzheimer disease-model transgenic mice (APP23 mouse), without a reduction in the brain beta-amyloid level. Moreover, treatment of APP23 mice with olmesartan decreased oxidative stress in brain microvessels. Using an acute mouse model induced by ICV administration of beta-amyloid 1-40, we assessed the effect of oral administration of olmesartan on spatial learning evaluated with the Morris water maze. Olmesartan significantly improved cognitive function independent of its blood pressure-lowering effect, whereas there was no improvement by other types of antihypertensive drugs (hydralazine and nifedipine). We found that pretreatment with a low dose of olmesartan completely prevented beta-amyloid-induced vascular dysregulation and partially attenuated the impairment of hippocampal synaptic plasticity. These findings suggest the possibility that amelioration of cerebrovascular dysfunction with an angiotensin receptor blocker could be a novel therapeutic strategy for the early stage of Alzheimer disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Angiotensin II Type 1 Receptor Blockers; Animals; Cerebrovascular Circulation; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Hippocampus; Imidazoles; Male; Maze Learning; Mice; Mice, Transgenic; Microcirculation; Neuronal Plasticity; Oxidative Stress; Peptide Fragments; Reactive Oxygen Species; Renin-Angiotensin System; Tetrazoles

Decreased cognitive function associated with coronary artery bypass graft surgery is common. These deficits may be similar to the cognitive dysfunction seen in the spectrum of mild cognitive impairment to Alzheimer's disease, which are believed to result from the accumulation of amyloid beta (Abeta) peptide in the brain. We measured cognition both before and after coronary artery bypass graft surgery and assayed Abeta levels to investigate whether the cognitive dysfunction of cardiac surgery was associated with Abeta levels.. The plasma of 332 patients, who had undergone neuropsychological testing before and 3 and 12 months after coronary artery bypass graft surgery, was analyzed for Abeta(42) and Abeta(40). Patients were classified as having preexisting cognitive impairment if cognitive function was decreased in two or more tests compared with a healthy control group, and postoperative cognitive dysfunction was defined as a decline in two or more tests compared with the group mean baseline score.. Preexisting cognitive impairment was present in 117 patients (35.2%), and postoperative cognitive dysfunction was present in 40 (12%) at 3 months and 41 (13%) at 12 months after surgery. Both plasma Abeta(42) and Abeta(40) levels assessed before the surgery were significantly lower in patients who later had postoperative cognitive dysfunction at 3 months.. Decreased preoperative plasma levels of Abeta(42) and Abeta(40) in patients who exhibit postoperative cognitive dysfunction at 3 months suggest that postoperative cognitive dysfunction at this time may share a common mechanism with mild cognitive impairment and Alzheimer's disease. This process may be exacerbated by anesthesia.

Topics: Aged; Amyloid beta-Peptides; Cognition Disorders; Coronary Artery Bypass; Female; Humans; Male; Neuropsychological Tests; Peptide Fragments; Time Factors

Topics: Amyloid beta-Peptides; Cognition Disorders; Coronary Artery Bypass; Humans; Neuropsychological Tests; Peptide Fragments

To longitudinally evaluate five cerebrospinal fluid (CSF) biomarkers in the transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD).. A baseline and 2-year follow-up clinical and CSF study of 86 subjects, including 22 MCI patients that declined to AD (MCI-AD), 43 MCI that did not deteriorate (MCI-MCI) and 21 controls (NL-NL). All subjects were studied for total and phosphorylated tau (T-tau, P-tau(231)), amyloid beta (Abeta) Abeta(42)/Abeta(40) ratio, isoprostane (IP) as well as P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios.. At baseline and at follow-up MCI-AD showed higher levels P-tau(231), T-tau, IP, P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios and lower Abeta(42)/Abeta(40) than MCI-MCI or NL-NL. Baseline P-tau(231) best predicted MCI-AD (80%, p<0.001) followed in accuracy by P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios (both 75%, p's<0.001), T-tau (74%, p<0.001), Abeta(42)/Abeta(40) (69%, p<0.01), and IP (68%, p<0.01). Only IP showed longitudinal effects (p<0.05).. P-tau(231) is the strongest predictor of the decline from MCI to AD. IP levels uniquely show longitudinal progression effects. These results suggest the use of CSF biomarkers in secondary prevention trials.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognition Disorders; Cohort Studies; Disease Progression; Early Diagnosis; Female; Humans; Isoprostanes; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Predictive Value of Tests; Prognosis; tau Proteins

Though elevated beta-amyloid deposition is associated with Alzheimer's disease, recent evidence suggests beta-amyloid is elevated in healthy older adults prior to the onset of Alzheimer's disease. No study has yet investigated whether reduced cognitive function is related to beta-amyloid elevation in healthy older adults. Thirty-five healthy older adults underwent neuropsychological testing and fasting blood draw with subsequent serum beta-amyloid 1-40 level quantification. beta-amyloid was negatively correlated with several aspects of cognition. Findings indicate that beta-amyloid level is associated with cognitive function in healthy older adults in a pattern similar to early Alzheimer's disease. Further work investigating possible mechanisms is needed.

Topics: Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Cognition Disorders; Female; Geriatric Assessment; Humans; Male; Neuropsychological Tests; Peptide Fragments; Sampling Studies; Self Concept

Memory loss is the signature feature of Alzheimer's disease, and therapies that prevent or delay its onset are urgently needed. Effective preventive strategies likely offer the greatest and most widespread benefits. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance memory and synaptic plasticity. We evaluated the efficacy of nicotinamide, a competitive inhibitor of the sirtuins or class III NAD(+)-dependent HDACs in 3xTg-AD mice, and found that it restored cognitive deficits associated with pathology. Nicotinamide selectively reduces a specific phospho-species of tau (Thr231) that is associated with microtubule depolymerization, in a manner similar to inhibition of SirT1. Nicotinamide also dramatically increased acetylated alpha-tubulin, a primary substrate of SirT2, and MAP2c, both of which are linked to increased microtubule stability. Reduced phosphoThr231-tau was related to a reduction of monoubiquitin-conjugated tau, suggesting that this posttranslationally modified form of tau may be rapidly degraded. Overexpression of a Thr231-phospho-mimic tau in vitro increased clearance and decreased accumulation of tau compared with wild-type tau. These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies, and that phosphorylation of tau at Thr231 may regulate tau stability.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Behavior, Animal; Butyrates; Cell Line, Transformed; Cognition Disorders; Disease Models, Animal; Enzyme Inhibitors; Humans; Immunoprecipitation; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubule-Associated Proteins; Mutation; Niacinamide; Peptide Fragments; Phosphorylation; Presenilin-1; Sirtuins; tau Proteins; Threonine; Time Factors; Transfection; Tubulin; Vitamin B Complex

Identifying individuals at high risk of developing Alzheimer's disease (AD) is important for future therapeutic strategies, and there is a clinical need for diagnostic biomarkers to identify incipient AD.. The aim of the present study was to investigate if the AD-associated Abeta peptide pattern recently found in cerebrospinal fluid (CSF) could discriminate between patients with incipient AD and those with stable mild cognitive impairment (MCI) by analyzing CSF from patients with MCI at baseline.. The levels of Abeta(1-37, -38, -39, -40, -42) were analyzed by Abeta-SDS-PAGE/immunoblot in CSF from 19 healthy controls, 25 patients with stable MCI and from 25 patients with MCI who later developed AD during 4- to 6-year follow-up.. All healthy controls and 20 out of 22 patients who developed AD were correctly classified by their baseline Abeta peptide pattern. In 9 out of 25 stable MCI patients, the pattern indicated incipient AD in spite of clinical nonconversion. Interestingly, these individuals had apolipoprotein E genotypes and CSF levels of tau and phospho-tau that are known to be associated with high risk of AD.. Altogether, our study reveals the novel finding that the Abeta peptide pattern is able to predict AD in patients with MCI with a sensitivity of 91% and specificity of 64%. The specificity would increase to 94% if the high-risk patients in the stable MCI cohort developed AD during extended follow-up.

Topics: Aged; Aged, 80 and over; Alleles; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Cognition Disorders; Disease Progression; Female; Follow-Up Studies; Humans; Male; Middle Aged; Peptide Fragments; Predictive Value of Tests; Sensitivity and Specificity; tau Proteins

Considerable evidence supports the role of oxidative stress in the pathogenesis of Alzheimer's disease (AD). Previous studies suggest that the central nervous system (CNS) administration of beta-amyloid peptide, the major constituent of senile plaque in AD, induces oxidative stress in rodents which may contribute to the learning and memory deficits verified in the beta-amyloid model of AD. In the present study, we compared the effects of a single intracerebroventricular (i.c.v.) injection of aggregated beta-amyloid peptide-(1-40) (Abeta(1-40)) (400pmol/mouse) on spatial learning and memory performance, synaptic density and the glutathione (GSH)-dependent antioxidant status in adult male C57BL/6 and Swiss albino mice. Seven days after Abeta(1-40) administration, C57BL/6 and Swiss mice presented similar spatial learning and memory impairments, as evaluated in the water maze task, although these impairments were not found in Abeta(40-1)-treated mice. Moreover, a similar decline of synaptophysin levels was observed in the hippocampus (HC) and prefrontal cortex (PFC) of both Swiss and C57BL/6 mice treated with Abeta(1-40), which suggests synaptic loss. C57BL/6 mice presented lower levels of glutathione-related antioxidant defences (total glutathione (GSH-t) levels, glutathione peroxidase (GPx) and glutathione reductase (GR) activity) in the HC and PFC in comparison to Swiss mice. Despite the reduced basal GSH-dependent antioxidant defences observed in C57BL/6 mice, Abeta(1-40) administration induced significant alterations in the brain antioxidant parameters only in Swiss mice, decreasing GSH-t levels and increasing GPx and GR activity in the HC and PFC 24h after treatment. These results indicate strain differences in the susceptibility to Abeta(1-40)-induced changes in the GSH-dependent antioxidant defences in mice, which should be taken into account in further studies using the Abeta model of AD in mice. In addition, the present findings suggest that the spatial learning and memory deficits induced by beta-amyloid peptides in rodents may not be entirely related to glutathione-dependent antioxidant response.

Topics: Amyloid beta-Peptides; Animals; Behavior, Animal; Cognition Disorders; Disease Susceptibility; Exploratory Behavior; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Immunohistochemistry; Injections, Intraventricular; Male; Maze Learning; Mice; Mice, Inbred C57BL; Peptide Fragments; Reaction Time; Space Perception; Species Specificity

To develop preventive therapy for Alzheimer disease (AD), it is essential to develop AD-related biomarkers that identify at-risk individuals in the same way that cholesterol levels identify persons at risk for heart disease.. To determine whether plasma levels of amyloid beta protein (Abeta40 and Abeta42) are useful for identifying cognitively normal elderly white subjects at increased risk for mild cognitive impairment (MCI) and AD.. Using well-established sandwich enzyme-linked immunosorbent assays, plasma Abeta40 and Abeta42 levels were analyzed at baseline in a prospective, elderly white cohort followed up for 2 to 12 (median, 3.7) years to detect incident cases of MCI or AD.. Cognitively normal, community-based white volunteers recruited from primary care settings into the Mayo Rochester Alzheimer Disease Patient Registry. Patients We followed up 563 cognitively normal white volunteers (median age, 78 years; 62% female) who had at least 1 follow-up visit after measurement of baseline plasma Abeta levels.. The primary outcome was time to development of MCI or AD. The secondary outcome was the annualized rate of cognitive change in patients for whom we had 2 Mattis Dementia Rating Scale evaluations 3 to 7 years apart.. During follow-up, 53 subjects developed MCI or AD. Subjects with plasma Abeta42/Abeta40 ratios in the lower quartiles showed significantly greater risk of MCI or AD (P = .04, adjusted for age and apolipoprotein E genotype). Comparison of subjects with plasma Abeta42/Abeta40 ratios in the lowest vs the highest quartile gave a relative risk of 3.1 (95% confidence interval, 1.1-8.3). After adjusting for age and apolipoprotein E genotype, regression analysis using annualized changes in the Dementia Rating Scale scores as an outcome variable showed that participants with lower Abeta42/Abeta40 ratios had greater cognitive decline (P = .02).. The plasma Abeta42/Abeta40 ratio may be a useful premorbid biomarker for identifying cognitively normal elderly white subjects who are at increased risk for developing MCI or AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cognition Disorders; Enzyme-Linked Immunosorbent Assay; Female; Geriatric Assessment; Humans; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Proportional Hazards Models; Residence Characteristics; Retrospective Studies; Risk

Evidence supports an important role for beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD). Here, we investigate baseline levels of the 40- and 42-amino-acid-long Abeta peptides (Abeta40 and Abeta42) in cerebrospinal fluid (CSF) from a cohort of patients with mild cognitive impairment (MCI, n = 137) in relation to the final diagnosis after 4-6 years of follow-up time. CSF Abeta42 concentration at baseline and the Abeta42/Abeta40 ratio were significantly decreased in the MCI patients who developed AD as compared to cognitively stable MCI patients and MCI patients who developed other forms of dementia (p < 0.001). The baseline levels of Abeta40 were similar in all MCI groups but correlated with change in Mini Mental State Examination scores in converters to AD. The Abeta42/Abeta40 ratio was superior to Abeta42 concentration with regard to identifying incipient AD in MCI (p < 0.05). In conclusion, the data provide further support for the view that amyloid precursor protein metabolism is disturbed in early sporadic AD and points to the usefulness of the Abeta42/Abeta40 ratio as a predictive biomarker for AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Biomarkers; Case-Control Studies; Cognition Disorders; Cohort Studies; Female; Humans; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Predictive Value of Tests; Reference Values; Risk Factors; Severity of Illness Index; Statistics, Nonparametric

In the past years, the possible involvement of inflammation in the pathogenesis of dementia has been the subject of several investigations. However there are restricted data about the profile of the inflammatory and soluble proteins in well evaluated Alzheimer's disease (AD), vascular dementia (VD), mild cognitive impairment (MCI) and healthy controls. There are also no reliable data regarding the relationship between the overlapping protein levels and cognitive or functional decline. We measured levels of IL-1beta, IL-2, IL-6, IL-18, TNF-alpha, beta-Amlyloid 1-40 and alpha1-antichymotrypsin levels in plasma in groups of total 82 subjects with AD, MCI, VD and controls using enzyme-linked immunosorbent assay (ELISA) method. Our study samples showed high levels of proinflammatory cytokine levels (especially IL-18) in all patient groups but only high levels of alpha1-antichymotrypsine in VD patients compared to controls. There is no significant correlation between the laboratory and clinical variables except for a link between IL-1beta and NPI scores of AD. In conclusion, this study yielded evidence of some shared mechanisms underlying AD and VD and thus motivates further studies of inflammatory markers in various types of dementia and MCI.

Topics: Acute-Phase Proteins; Aged; Amyloid beta-Peptides; Analysis of Variance; Biomarkers; Case-Control Studies; Cognition Disorders; Cross-Sectional Studies; Dementia; Diagnosis, Differential; Female; Humans; Interleukins; Male; Matched-Pair Analysis; Middle Aged; Peptide Fragments; Reference Values; Severity of Illness Index; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

Transgenic mice expressing mutant forms of both amyloid-beta (Abeta) precursor protein (APP) and presenilin (PS) 2 develop severe brain amyloidosis and cognitive deficits, two pathological hallmarks of Alzheimer's disease (AD). One-year-old APP/PS2 mice with high brain levels of Abeta and abundant Abeta plaques show disturbances in spatial learning and memory. Treatment of these deteriorated mice with a systemic slow-release formulation of insulin-like growth factor I (IGF-I) significantly ameliorated AD-like disturbances. Thus, IGF-I enhanced cognitive performance, decreased brain Abeta load, increased the levels of synaptic proteins, and reduced astrogliosis associated to Abeta plaques. The beneficial effects of IGF-I were associated to a significant increase in brain Abeta complexed to protein carriers such as albumin, apolipoprotein J or transthyretin. Since levels of APP were not modified after IGF-I therapy, and in vitro data showed that IGF-I increases the transport of Abeta/carrier protein complexes through the choroid plexus barrier, it seems that IGF-I favors elimination of Abeta from the brain, supporting a therapeutic use of this growth factor in AD.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidosis; Analysis of Variance; Animals; Behavior, Animal; Blood-Brain Barrier; Brain Chemistry; Brain Diseases; Cognition Disorders; Disease Models, Animal; Immunohistochemistry; Insulin-Like Growth Factor I; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Spatial Behavior

Microvascular brain injury, typically measured by extent of white matter hyperintensity (WMH) on MRI, is an important contributor to cognitive impairment in the elderly. Recent studies suggest a role for circulating beta-amyloid peptide in microvascular dysfunction and white matter disease.. The authors performed a cross-sectional study of clinical, biochemical, and genetic factors associated with WMH in 54 subjects with Alzheimer disease (AD) or mild cognitive impairment (AD/MCI) and an independent group of 42 subjects with cerebral amyloid angiopathy (CAA). Extent of WMH was determined by computer-assisted volumetric measurement normalized to intracranial size (nWMH). Biochemical measurements included plasma concentrations of the 40- and 42-amino acid species of beta-amyloid (Abeta40 and Abeta42) detected by specific enzyme-linked immunosorbent assays.. Plasma Abeta40 concentrations were associated with nWMH in both groups (correlation coefficient = 0.48 in AD/MCI, 0.42 in CAA, p < or = 0.005). Plasma Abeta40 remained independently associated with nWMH after adjustment for potential confounders among age, hypertension, diabetes, homocysteine, creatinine, folate, vitamin B12, and APOE genotype. The presence of lacunar infarctions was also associated with increased Abeta40 in both groups. nWMH was greater in CAA (19.8 cm3) than AD (11.1 cm3) or MCI (10.0 cm3; p < 0.05 for both comparisons).. Plasma beta-amyloid 40 concentration is independently associated with extent of white matter hyperintensity in subjects with Alzheimer disease, mild cognitive impairment, or cerebral amyloid angiopathy. If confirmed in longitudinal studies, these data would suggest circulating beta-amyloid peptide as a novel biomarker or risk factor for microvascular damage in these common diseases of the elderly.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Brain Infarction; Cerebral Amyloid Angiopathy; Cerebral Arteries; Cerebrovascular Disorders; Cognition Disorders; Cross-Sectional Studies; Female; Humans; Male; Microcirculation; Middle Aged; Nerve Fibers, Myelinated; Peptide Fragments; Predictive Value of Tests; Prognosis

A recent epidemiological study suggested that higher caffeine intake over decades reduces the risk of Alzheimer's disease (AD). The present study sought to determine any long-term protective effects of dietary caffeine intake in a controlled longitudinal study involving AD transgenic mice. Caffeine (an adenosine receptor antagonist) was added to the drinking water of amyloid precursor protein, Swedish mutation (APPsw) transgenic (Tg) mice between 4 and 9 months of age, with behavioral testing done during the final 6 weeks of treatment. The average daily intake of caffeine per mouse (1.5 mg) was the human equivalent of 500 mg caffeine, the amount typically found in five cups of coffee per day. Across multiple cognitive tasks of spatial learning/reference memory, working memory, and recognition/identification, Tg mice given caffeine performed significantly better than Tg control mice and similar to non-transgenic controls. In both behaviorally-tested and aged Tg mice, long-term caffeine administration resulted in lower hippocampal beta-amyloid (Abeta) levels. Expression of both Presenilin 1 (PS1) and beta-secretase (BACE) was reduced in caffeine-treated Tg mice, indicating decreased Abeta production as a likely mechanism of caffeine's cognitive protection. The ability of caffeine to reduce Abeta production was confirmed in SweAPP N2a neuronal cultures, wherein concentration-dependent decreases in both Abeta1-40 and Abeta1-42 were observed. Although adenosine A(1) or A(2A) receptor densities in cortex or hippocampus were not affected by caffeine treatment, brain adenosine levels in Tg mice were restored back to normal by dietary caffeine and could be involved in the cognitive protection provided by caffeine. Our data demonstrate that moderate daily intake of caffeine may delay or reduce the risk of AD.

Topics: Adenosine; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Brain; Caffeine; Cell Line, Tumor; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Memory Disorders; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Neuropsychological Tests; Peptide Fragments; Presenilin-1; Purinergic P1 Receptor Antagonists; Receptors, Purinergic P1; Treatment Outcome

Plasma alpha beta levels have been examined in sporadic Alzheimer's disease yielding conflicting results; both no difference and an increase in plasma concentrations of alpha beta42 and alpha beta40 in sporadic cases of AD as compared to controls have been reported. Elevated plasma alpha beta42 levels may be detected several years before the onset of symptoms (in mild cognitive impairment stadium). Levels of alpha beta40 and alpha beta42 were measured in plasma from 54 patients with AD, 39 subjects with MCI and 35 controls using a commercially available ELISA. Mean plasma alpha beta42 levels were significantly higher in MCI as compared to both AD (P < 0.001) and control subjects (P < 0.001), while alpha beta40 did not differ between the groups. No correlations were observed between alpha beta levels and age, MMSE scores or gender. According to ROC curve analysis the maximum accuracy in discriminating MCI versus both controls and AD subjects has been achieved using a cut-off value of 3.8.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Case-Control Studies; Cognition Disorders; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Peptide Fragments; ROC Curve

Increasing evidence points to synaptic plasticity impairment as one of the first events in Alzheimer's disease (AD). However, studies on synaptic dysfunction in different transgenic AD models that overexpress familial AD mutant forms of amyloid precursor protein (APP) and/or presenilin (PS) have provided conflicting results. Both long-term potentiation (LTP) and basal synaptic transmission (BST) have been found to be both unchanged and altered in different models and under differing experimental conditions. Because of their more robust amyloid-beta (Abeta) deposition, double transgenic mice currently are used by several laboratories as an AD model. Here, we report that mice overexpressing APP (K670N:M671L) together with PS1 (M146L) have abnormal LTP as early as 3 months of age. Interestingly, reduced LTP paralleled plaque appearance and increased Abeta levels and abnormal short-term memory (working memory). BST and long-term memory (reference memory) are impaired only later (approximately 6 months) as amyloid burden increases. Abeta pathology across different ages did not correlate with synaptic and cognitive deficits, suggesting that Abeta levels are not a marker of memory decline. In contrast, progression of LTP impairment correlated with the deterioration of working memory, suggesting that percentage of potentiation might be an indicator of the cognitive decline and disease progression in the APP/PS1 mice.

Topics: Age Factors; Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Animals, Newborn; Brain Chemistry; Cognition Disorders; Disease Models, Animal; Disease Progression; Electric Stimulation; Enzyme-Linked Immunosorbent Assay; Excitatory Postsynaptic Potentials; Hippocampus; Humans; In Vitro Techniques; Long-Term Potentiation; Membrane Proteins; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondrial Proteins; Peptide Fragments; Time Factors

Traumatic brain injury is a well-recognized environmental risk factor for developing Alzheimer's disease. Repetitive concussive brain injury (RCBI) exacerbates brain lipid peroxidation, accelerates amyloid (Abeta) formation and deposition, as well as cognitive impairments in Tg2576 mice. This study evaluated the effects of vitamin E on these four parameters in Tg2576 mice following RCBI. Eleven-month-old mice were randomized to receive either regular chow or chow-supplemented with vitamin E for 4 weeks, and subjected to RCBI (two injuries, 24 h apart) using a modified controlled cortical impact model of closed head injury. The same dietary regimens were maintained up to 8 weeks post-injury, when the animals were killed for biochemical and immunohistochemical analyses after behavioral evaluation. Vitamin E-treated animals showed a significant increase in brain vitamin E levels and a significant decrease in brain lipid peroxidation levels. After RBCI, compared with the group on regular chow, animals receiving vitamin E did not show the increase in Abeta peptides, and had a significant attenuation of learning deficits. This study suggests that the exacerbation of brain oxidative stress following RCBI plays a mechanistic role in accelerating Alphabeta accumulation and behavioral impairments in the Tg2576 mice.

Topics: Amyloid; Amyloid beta-Peptides; Amyloidosis; Animals; Antioxidants; Brain; Brain Chemistry; Brain Concussion; Cognition Disorders; Dietary Supplements; Dinoprost; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Mice; Mice, Transgenic; Motor Activity; Oxidative Stress; Peptide Fragments; Vitamin E

Accumulation in the brain of small aggregates of amyloid beta-protein 42 (Abeta42) is the major pathogenic event of Alzheimer disease (AD). In familial early-onset AD this event is likely the result of Abeta42 overproduction; in the most common sporadic late-onset form of the disease the mechanisms of Abeta42 accumulation are unknown.. To address this issue the authors analyzed plasma levels of Abeta42 in 88 elderly patients with amnestic mild cognitive impairment (MCI), chosen as paradigm of preclinical sporadic AD.. The authors found a significant increase of Abeta42 plasma levels in women with MCI, in comparison to the affected men and 72 cognitively normal age-matched subjects. The levels were independent of variables in education, apolipoprotein E genotype, cholesterol, and creatinine plasma concentrations, as well as hemoglobin content.. The elevation of Abeta42 plasma levels in women with MCI may represent a biologic explanation for the sex-dependent increased incidence of late-onset AD in women identified by epidemiologic studies.

Topics: Age of Onset; Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Biomarkers; Cholesterol; Cognition Disorders; Creatine; Educational Status; Female; Hemoglobins; Humans; Incidence; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Peptide Fragments; Sex Distribution

Severe cognitive impairment is common in elderly patients with schizophrenia. Alzheimer's disease is the main cause of dementia among the elderly. Biochemical and genetic studies suggest that amyloid beta-peptide is central in Alzheimer's disease. The authors examined the possible involvement of amyloid beta-peptide in cognitive impairment in schizophrenia.. Specific antibodies against two major forms of amyloid beta-peptide, Abetax-40 and Abetax-42, were used in sandwich enzyme-linked immunosorbent assays to determine the levels of amyloid beta-peptide in postmortem brain samples from Alzheimer's disease patients (N=10), normal elderly comparison subjects (N=11), and schizophrenia patients with (N=7) or without (N=26) Alzheimer's disease.. The levels of amyloid beta-peptide were highest in the Alzheimer's disease patients, followed by the patients with schizophrenia and comparison subjects. The mean Abetax-42 level in the schizophrenia patients without Alzheimer's disease was similar to that in the comparison subjects, but the level in the schizophrenia patients with Alzheimer's disease was significantly higher than in those without Alzheimer's disease or the comparison subjects. The Abetax-42 level in the schizophrenia patients with Alzheimer's disease was significantly lower than the level in the Alzheimer's disease cohort.. In contrast to elderly schizophrenia patients with Alzheimer's disease pathology, those without Alzheimer's disease had amyloid beta-peptide levels that were not significantly different from those of normal subjects; hence amyloid beta-peptide does not account for the cognitive deficits in this group. These results suggest that the causes of cognitive impairment in "pure" schizophrenia are different from those in Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidosis; Brain Chemistry; Brain Diseases; Cognition Disorders; Comorbidity; Enzyme-Linked Immunosorbent Assay; Female; Geriatric Assessment; Humans; Male; Peptide Fragments; Plaque, Amyloid; Prefrontal Cortex; Schizophrenia

Excessive extracellular deposition of amyloid beta (Abeta) peptide in neuritic plaques and degeneration of forebrain cholinergic neurones, which innervate the hippocampus and the neocortex, are the invariant characteristic features of Alzheimer's disease (AD). Studies of the pathological changes that characterize AD, together with several other lines of evidence, indicate that Abeta accumulation in vivo may initiate and/or contribute to the process of neurodegeneration observed in the AD brain. However, the underlying mechanisms by which Abeta peptide influences/causes degeneration of the basal forebrain cholinergic neurones in AD brains remain obscure. We reported earlier that nM concentrations of Abeta-related peptides, under acute conditions, can potently inhibit K+-evoked endogenous acetylcholine (ACh) release from the hippocampus and the cortex but not from striatum in young adult rats (J. Neurosci. 16 (1996) 1034). In the present study, to determine whether the effects of Abeta peptides alter with normal aging and/or cognitive state, we have measured Abeta1-40 levels and the effects of exogenous Abeta1-40 on hippocampal ACh release in young adult as well as aged cognitively-unimpaired (AU) and -impaired (AI) rats. Endogenous levels of Abeta(1-40) in the hippocampus are significantly increased in aged rats. Additionally, 10 nM Abeta1-40 potently inhibited endogenous ACh release from the hippocampus of the three groups of rats, but the time-course of the effects clearly indicate that the cholinergic neurones of AI rats are more sensitive to Abeta peptides than either AU or young adult rats. These results, together with earlier reports, suggest that the processing of the precursor protein of Abeta peptide alters with normal aging and the response of the cholinergic neurones to the peptide possibly varies with the cognitive status of the animals.

Topics: Acetylcholine; Aging; Amyloid beta-Peptides; Animals; Behavior, Animal; Cognition Disorders; Hippocampus; Male; Peptide Fragments; Rats; Rats, Long-Evans

Huperzine A, a promising therapeutic agent for Alzheimer's disease, was examined for its potential to antagonize the deleterious neurochemical, structural, and cognitive effects of infusing beta-amyloid protein-(1-40) into the cerebral ventricles of rats. Daily intraperitoneal administration of huperzine A for 12 consecutive days produced significant reversals of the beta-amyloid-induced deficit in learning a water maze task. This treatment also reduced the loss of choline acetyltransferase activity in cerebral cortex, and the neuronal degeneration induced by beta-amyloid protein-(1-40). In addition, huperzine A partly reversed the down-regulation of anti-apoptotic Bcl-2 and the up-regulation of pro-apoptotic Bax and P53 proteins and reduced the apoptosis that normally followed beta-amyloid injection. The present findings confirm that huperzine A can alleviate the cognitive dysfunction induced by intracerebroventricular infusion of beta-amyloid protein-(1-40) in rats. The beneficial effects are not confined to the cholinergic system, but also include favorable changes in the expression of apoptosis-related proteins and in the extent of apoptosis in widespread regions of the brain.

Topics: Alkaloids; Amyloid beta-Peptides; Animals; Apoptosis; bcl-2-Associated X Protein; Cerebral Cortex; Choline O-Acetyltransferase; Cognition Disorders; Dose-Response Relationship, Drug; Hippocampus; Humans; In Situ Nick-End Labeling; Infusion Pumps; Injections, Intraventricular; Male; Maze Learning; Memory Disorders; Microscopy, Electron; Nerve Degeneration; Neurons; Neuroprotective Agents; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Sesquiterpenes; Tumor Suppressor Protein p53