amyloid-beta-peptides and Memory-Disorders

Plasma measurement of amyloid-β (Aβ) peptides has been associated with cognitive function, but evidence of its ability to identify cognitive decline is still scarce.. To investigate the associations between plasma Aβ42/40 and cognitive decline over time among community-dwelling older adults with subjective memory concerns.. This multicenter cohort study used data from volunteers in the 5-year study Multidomain Alzheimer Preventive Trial (MAPT). Participants were aged 70 years or older and observed for a median (interquartile range) of 3.9 (2.0-4.0) years. Recruitment of participants started in May 2008 and ended in February 2011. Follow-up ended in April 2016. Data analysis was conducted from April to October 2020.. Plasma Aβ42 and Aβ40 were measured at 12 months for 448 participants (92.8%) and at 24 months for the rest. The moment of Aβ assessment was defined as the baseline for this study.. Cognitive function was assessed at 12, 24, 36, 48, and 60 months by a composite cognitive score based on 4 tests; Mini Mental State Examination (MMSE); Clinical Dementia Rating, sum of boxes; and Alzheimer Disease Cooperative Study-Activities of Daily Living. Mixed-effect linear regressions were performed.. A total of 483 participants (median [IQR] age, 76.0 [73.0-80.0]; 286 [59.2%] women) were analyzed. Of them, 161 (33.3%) were classified as low plasma Aβ42/40 (≤0.107). After adjusting for age, sex, education, body mass index, Geriatric Depression Scale score, apolipoprotein E ε4 genotype, and MAPT intervention groups, low plasma Aβ42/40 was associated with more pronounced decline in composite cognitive score (adjusted between-group mean difference: -0.20, 95% CI, -0.34 to -0.07; P = .004) and decline in MMSE score (adjusted between-group mean difference: -0.59; 95% CI, -1.07 to -0.11; P = .02) during the follow-up period compared with the group with an Aβ42/40 ratio greater than 0.107.. In this study, low plasma Aβ42/40 was associated with more pronounced decline in cognitive function (measured by multiple outcomes) over time. Findings suggest that plasma Aβ42/40 may be used to identify people at risk of cognitive decline, being an alternative to more complex and expensive measures, such as positron emission tomography imaging or cerebrospinal fluid measurement.

Topics: Aged; Amyloid beta-Peptides; Apolipoprotein E4; Cognition; Cognitive Dysfunction; Correlation of Data; Diagnostic Self Evaluation; Female; Geriatric Assessment; Humans; Independent Living; Male; Memory Disorders; Peptide Fragments

Extensive data point to the immune system as an important factor underlying the pathogenesis of brain diseases. Epidemiological studies have shown that long-term treatment with non-steroidal anti-inflammatory drugs (NSAIDs) significantly reduces the onset and progression of Alzheimer's disease. The present study aimed to investigate whether ibuprofen (IBU) is able to prevent the long-lasting alterations of brain function induced by systemic inflammation.. Mice received intraperitoneal injections of lipopolysaccharide (LPS; 250 µg/kg/day) for seven consecutive days. Ibuprofen administration (40 mg/kg/day) was started three days before the LPS injections and continued until the last day of LPS injection. Within the next 2 weeks, mice performances on the behavioral tests were evaluated, and then brain tissue samples for biochemical analyses were collected.. The findings showed that ibuprofen significantly improved mice's performance in the passive avoidance test and reduced anxiety- and depressive-like behaviors. However, ibuprofen could not significantly improve spatial memory in the Morris water maze test and recognition ability in the novel object recognition test. TNF-α and IL-1β cytokines levels and malondialdehyde (MDA) concentration in the hippocampal tissues of LPS-treated mice were significantly lowered by ibuprofen treatment, whereas no significant effects on IL-10 production and hippocampal BDNF levels were observed. In addition, ibuprofen did not significantly reduce amyloid-β. Overall, the findings of the present study suggest that some, but not all, of the adverse effects of systemic inflammation are alleviated by ibuprofen treatment.

Topics: Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anxiety; Behavior, Animal; Brain; Cytokines; Depression; Encephalitis; Ibuprofen; Inflammation; Lipopolysaccharides; Male; Malondialdehyde; Memory Disorders; Mice; Mice, Inbred BALB C; Morris Water Maze Test; Peptide Fragments; Psychomotor Performance; Recognition, Psychology; Swimming

Alzheimer's disease (AD) is a neurodegenerative disease, in which the accumulation of β-amyloid (Aβ) peptide in the extracellular space causes a progressive reduction in cognitive performance. Aβ stimulates active oxygen species generation leading to oxidative stress and neural cell death. Vanillic Acid (VA) is the oxidant form of vanillin widely found in vanilla beans. VA has many properties, such as suppressing apoptosis and eliminating the harmful effects of oxidative stress in animal models. The VA effects on impaired learning and memory in Aβ rats were assessed. Forty adults male Wistar rats were assigned to the following five groups in random: the control, sham (received saline (vehicle) via intracerebroventricular (ICV) injection), Aβ (received Aβ1-40 via ICV injection), VA (50 mg/kg by oral gavage once a day through four weeks), and Aβ + VA (50 mg/kg) groups. Open field test, novel object recognition (NOR) test, Morris water maze (MWM) test, and passive avoidance learning (PAL) task were performed, and finally, we determined the malondialdehyde (MDA), total antioxidant capacity (TAC) and total oxidant status (TOS) levels. Aβ decreased the cognitive memory in NOR, spatial memory in MWM, and passive avoidance memory in PAL tests. In contrast, VA improved learning and memory in the treated group. Aβ significantly increased MDA and TOS and decreased TAC levels, whereas VA treatment significantly reversed TAC, TOS and MDA levels. In conclusion, VA decreased the Aβ effects on learning and memory by suppressing oxidative stress and can be regarded as a neuroprotective substance in AD.

Topics: Amyloid beta-Peptides; Animals; Avoidance Learning; Disease Models, Animal; Hippocampus; Learning; Male; Malondialdehyde; Memory; Memory Disorders; Neurons; Oxidative Stress; Peptide Fragments; Rats; Vanillic Acid

There is a scientific and operational need to define objective measures of exposure to low-level overpressure (LLOP) and concussion-like symptoms among persons with specialized occupations.. To evaluate serum levels of neurotrauma biomarkers and their association with concussion-like symptoms reported by LLOP-exposed military and law enforcement personnel who are outwardly healthy and cleared to perform duties.. This retrospective cohort study, conducted from January 23, 2017, to October 21, 2019, used serum samples and survey data collected from healthy, male, active-duty military and law enforcement personnel assigned to operational training at 4 US Department of Defense and civilian law enforcement training sites. Personnel aged 18 years or older with prior LLOP exposure but no diagnosed traumatic brain injury or with acute blast exposure during sampling participated in the study. Serum samples from 30 control individuals were obtained from a commercial vendor.. Serum levels of glial fibrillary acidic protein, ubiquitin carboxyl hydrolase (UCH)-L1, neurofilament light chain, tau, amyloid β (Aβ)-40, and Aβ-42 from a random sample (30 participants) of the LLOP-exposed cohort were compared with those of 30 age-matched controls. Associations between biomarker levels and self-reported symptoms or operational demographics in the remainder of the study cohort (76 participants) were assessed using generalized linear modeling or Spearman correlations with age as a covariate.. Among the 30 randomly sampled participants (mean [SD] age, 32 [7.75] years), serum levels of UCH-L1 (mean difference, 4.92; 95% CI, 0.71-9.14), tau (mean difference, 0.16; 95% CI, -0.06 to 0.39), Aβ-40 (mean difference, 138.44; 95% CI, 116.32-160.56), and Aβ-42 (mean difference, 4.97; 95% CI, 4.10-5.83) were elevated compared with those in controls. Among the remaining cohort of 76 participants (mean [SD] age, 34 [7.43] years), ear ringing was reported by 44 (58%) and memory or sleep problems were reported by 24 (32%) and 20 (26%), respectively. A total of 26 participants (34%) reported prior concussion. Amyloid β-42 levels were associated with ear ringing (F1,72 = 7.40; P = .008) and memory problems (F1,72 = 9.20; P = .003).. The findings suggest that long-term LLOP exposure acquired during occupational training may be associated with serum levels of neurotrauma biomarkers. Assessment of biomarkers and concussion-like symptoms among personnel considered healthy at the time of sampling may be useful for military occupational medicine risk management.

Topics: Adult; Amyloid beta-Peptides; Atmospheric Pressure; Biomarkers; Brain Injuries, Traumatic; Case-Control Studies; Glial Fibrillary Acidic Protein; Headache; Humans; Male; Memory Disorders; Military Personnel; Neurofilament Proteins; Occupational Exposure; Peptide Fragments; Police; Pressure; Self Report; tau Proteins; Tinnitus; Ubiquitin Thiolesterase

The present study was conducted to evaluate the efficacy of fenofibrate and pioglitazone in a mouse model of amyloidogenesis induced by amyloidβ (βA) peptide. Mice were injected intracerebroventricularly with βA1-40 (400 pmol/mouse) once, followed by treatment with fenofibrate (300 mg/kg), pioglitazone (30 mg/kg),or both. After 21 days of daily treatment, memory impairment and cognitive function were evaluated by Morris water maze (MWM), Y-maze and object recognition tests. On the 22nd day, mice were sacrificed, and their hippocampi were dissected to determine the levels of α- and β-secretase, peroxisome proliferator-activated receptor (PPARα and β), Wnt and β-catenin. Significant memory impairment and cognitive dysfunction were observed in the mouse model group. This finding was associated with a significant increase in α- and β-secretase levels and a significant decrease in Wnt, β-catenin, and PPARα and β levels. Neuronal damage was also evident after histopathological examination. Treatment with fenofibrate, pioglitazone and their combination resulted in a significant improvement in the behavioural and neurochemical changes induced by βA injection. The present findings indicate that the combined administration of fenofibrate and pioglitazone was more effective than monotherapy in ameliorating the behavioural, neurochemical and histopathological changes in amyloidogenesis model mice and provide a promising therapeutic approach in the management of Alzheimer's disease complicated by diabetes and hypercholesterolemia.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Cognitive Dysfunction; Fenofibrate; Hippocampus; Infusions, Intraventricular; Male; Memory Disorders; Mice; Neuroprotective Agents; Peptide Fragments; Pioglitazone; PPAR alpha; PPAR gamma; Wnt Signaling Pathway

An antioxidant polysaccharide, porphyran, from red algae Pyropia haitanensis, is introduced as a protective agent against neurotoxicity-induced amyloid β peptide (Aβ) of Alzheimer's disease (AD) mice. Then the activity of acetylcholinesterase (AChE) and choline acetyltransferase (CHAT) in the cortical and hippocampal tissue were examined by colorimetric method. Results showed that porphyran significantly ameliorated the learning and memory impairment induced by Aβ

Topics: Acetylcholine; Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Choline O-Acetyltransferase; Hippocampus; Male; Maze Learning; Memory; Memory Disorders; Mice; Neuroprotective Agents; Peptide Fragments; Polysaccharides; Rhodophyta; Sepharose

Lactoferrin (LF) is present in senile plaques and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients and amyloid-β protein precursor transgenic (AβPP-Tg) mice. LF has anti-inflammatory and antioxidant functions, which exert neuroprotective effects against AD. However, its effects on memory impairment and AD pathogenesis have not been fully examined. In this study, we examined the effects of LF on memory impairment and AD pathogenesis in AβPP-Tg mice (J20 mice). Nine-month-old J20 mice were fed with control, 2% lactoferrin-containing (LF), and 0.5% pepsin-hydrolyzed lactoferrin-containing (LF-hyd) diets for 3 months. We found that both the LF and LF-hyd diets attenuated memory impairment in J20 mice and decreased brain Aβ40 and Aβ42 levels through the inhibition of amyloidogenic processing of AβPP, as it decreased β-site amyloid protein precursor cleaving enzyme 1 (BACE1) levels. Furthermore, we found for the first time that LF and LF-hyd treatments increased both ApoE secretion and ATP-binding cassette A1 (ABCA1) protein levels in the brains of J20 mice and in primary astrocyte cultures. Moreover, LF and LF-hyd promoted extracellular degradation of Aβ in primary astrocyte cultures. These findings indicate that the reduction in Aβ levels in the brains of mice fed with both the LF and LF-hyd diets may also be mediated by increased ApoE secretion and ABCA1 protein levels, which in turn leads to the enhanced degradation of Aβ in the brains of J20 mice. Our findings suggest that LF and LF-hyd can be used for the treatment and/or prevention of the development of AD.

Topics: Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Apolipoproteins E; Aspartic Acid Endopeptidases; Astrocytes; ATP Binding Cassette Transporter 1; Brain Chemistry; Diet; Dietary Supplements; Humans; Lactoferrin; MAP Kinase Signaling System; Memory Disorders; Mice; Mice, Transgenic; Peptide Fragments; Primary Cell Culture; Rats; Rats, Wistar

Assessment of hippocampal amnesia is helpful to distinguish between normal cognition and mild cognitive impairment (MCI), but not for identifying converters to dementia. Here biomarkers are useful but novel neuropsychological approaches are needed in their absence. The In-out-test assesses episodic memory using a new paradigm hypothesized to avoid reliance on executive function, which may compensate for damaged memory networks.. To assess the validity of the In-out-test in identifying prodromal Alzheimer's disease (PAD) in a clinical setting, by comparing this to the Free and Cued Selective Reminding Test (FCSRT) and cerebrospinal fluid biomarkers.. A cross-sectional study of 32 cognitively healthy, 32 MCI, and 30 progressive dementia subjects. All participants were given both the In-out-test and the FCSRT; 40 of them also received a lumbar puncture.. Internal consistency was demonstrated using Cronbach Alpha (r = 0.81) and Inter-rater reliability with Kappa (k = 0.94). Intraclass correlation (ICC) for test-retest reliability: r = 0.57 (p = 0.57). ICC between the In-out-test and FCSRT r = 0.87 (p = 0.001). ICC between the In-out-test and Aβ42 and P-tau/Aβ42 for controls: 0.73 and 0.75, respectively; P-tau for MCI: 0.77 and total sample: 0.70; Aβ42 for dementia: 0.71. All ICC measures between FCSRT and biomarkers were ≤0.264. AD diagnosis: In-out-test k = 0.71; FCSRT k = 0.49. PAD diagnosis (N = 35): In-out-test k = 0.69; FCSRT k = 0.44.. The In-out-test detected prodromal AD with a higher degree of accuracy than a conventional hippocampal-based memory test. These results suggest that this new paradigm could be of value in clinical settings, predicting which patients with MCI will go on to develop AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Cues; Female; Humans; Male; Memory Disorders; Memory, Episodic; Middle Aged; Neuropsychological Tests; Peptide Fragments; Reproducibility of Results; tau Proteins

 Alzheimer's disease (AD) is one of the most common neurodegenerative pathologies for which there are no effective therapies to halt disease progression. Given the increase in the incidence of this disorder, there is an urgent need for pharmacological intervention. Unfortunately, recent clinical trials produced disappointing results. Molecular mechanisms of AD are converging on the notion that mitochondrial dysfunction, oxidative stress, and accumulation of dysfunctional proteins are involved in AD pathology. Previously, we have shown that a water-soluble formulation of Coenzyme Q10 (Ubisol-Q10), an integral part of the electron transport chain, stabilizes mitochondria and prevents neuronal cell death caused by neurotoxins or oxidative stress both in vitro and in vivo. In this study, we evaluated the neuroprotective effects of Ubisol-Q10 treatment in double transgenic AD mice. In the present study, we report that providing Ubisol-Q10 in drinking water (at a dose of ∼6 mg/kg/day) reduced circulating amyloid-β (Aβ) peptide, improved long term memory, preserved working spatial memory, and drastically inhibited Aβ plaque formation in 18-month-old transgenic mice compared to an untreated transgenic group. Thus Ubisol-Q10 supplementation has the potential to inhibit the progression of neurodegeneration, leading to a better quality of life for humans suffering with AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Male; Maze Learning; Memory; Memory Disorders; Mice; Mice, Transgenic; Microglia; Mutation; Nerve Tissue Proteins; Peptide Fragments; Presenilin-1; Ubiquinone; Vitamins

The transient receptor potential cation (TRPC) channels are widely expressed in nervous system but their functions remain largely unclear. Here, we found that TRPC1 deletion did not affect learning and memory in physiological conditions, while it aggravated learning and memory deficits induced by amyloid-β (Aβ), the major component of the senile plaques observed in the brains of Alzheimer's disease (AD). Further studies demonstrated that TRPC1 deletion did not affect cell apoptosis in physiological condition, but it exacerbated the Aβ-induced cell death in mouse hippocampus. Moreover, the level of TRPC1 was decreased in AD cell and mouse models, and upregulation of TRPC1 decreased Aβ levels with attenuation of apoptosis in the cells stably overexpressing amyloid-β protein precursor (AβPP). Finally, the transmembrane domain of TRPC1 could bind to AβPP and thus decreased Aβ production. These findings indicate that loss of TRPC1 exacerbates Aβ-induced memory deficit and cell apoptosis, though it does not impair cognitive function or induce cell death in physiological conditions.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Cell Line, Tumor; Disease Models, Animal; HEK293 Cells; Hippocampus; Humans; Learning; Male; Memory; Memory Disorders; Mice, 129 Strain; Mice, Knockout; Peptide Fragments; Protein Domains; TRPC Cation Channels

Silent glutamatergic synapses lacking functional AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate) receptors exist in several brain regions including the hippocampus. Their involvement in the dysfunction of hippocampal glutamatergic transmission in the setting of Alzheimer's disease (AD) is unknown. This study demonstrated a decrease in the percentage of silent synapses in rats microinjected with amyloid fibrils (Aβ

Topics: Amyloid; Amyloid beta-Peptides; Animals; CA1 Region, Hippocampal; Cofilin 1; Disease Models, Animal; Disks Large Homolog 4 Protein; Electric Stimulation; Gene Expression Regulation; Glutamic Acid; In Vitro Techniques; Long-Term Potentiation; Male; Maze Learning; Memory Disorders; Patch-Clamp Techniques; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Synapses; Synaptosomes

Chronic cerebral hypoperfusion is considered as a pivotal factor of cognitive impairment that occurs in cerebrovascular diseases. This study investigated the ameliorating effect of scutellarin (SCT) on spatial cognitive impairment and β-amyloid (Aβ) formation in rats with chronic cerebral hypoperfusion induced by permanent bilateral common carotid artery occlusion (pBCAO). SCT is a flavonoid in medicinal herb of Erigeron breviscapus (vant.) Hand. Mazz. known to have neuroprotective, antioxidative and anti-inflammatory effects. However, the beneficial effect and pivotal mechanism of SCT on cognitive impairment are still unclear. SCT was treated orally with two doses (10 or 30 mg/kg) for 4 weeks. Results of Morris water maze test performed on the ninth week after pBCAO revealed that SCT (30 mg/kg)-treated rats had significantly shortened escape latencies in acquisition training trials, significantly prolonged swimming time at the platform and its surrounding zone, significant increase in memory score, significant reduction in the number of target heading, and significant reduction in the time required for the first target heading during the retention trial compared to rats in the sham-control group. SCT significantly inhibited the production of Aβ(1-40) and Aβ(1–42) in brain tissues. However, SCT significantly upregulated the expression levels of amyloid precursor protein and β-site APP-converting enzyme-1 in the hippocampus. In addition, SCT significantly inhibited the activation of Iba1-expressing microglia in brain tissues. The results suggest that SCT can exert ameliorating effect on spatial cognitive impairment caused by chronic cerebral hypoperfusion through suppressing Aβ formation and microglial activation in brain tissues. Therefore, SCT can be used as a beneficial drug for vascular dementia and Alzheimer's disease.

Topics: Administration, Oral; Amyloid beta-Peptides; Animals; Apigenin; Brain; Calcium-Binding Proteins; Chronic Disease; Erigeron; Glucuronates; Hypoxia-Ischemia, Brain; Learning Disabilities; Male; Memory Disorders; Microfilament Proteins; Microglia; Peptide Fragments; Phytotherapy; Rats, Sprague-Dawley

Alzheimer's disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid β (Aβ) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti-amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed. The efficacy of the designed peptide, R

Topics: Administration, Intranasal; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Brain; Cell Line; Cognition; Cognitive Dysfunction; Disease Models, Animal; Female; Memory Disorders; Mice, Inbred C57BL; Peptide Fragments; Peptides

Diabetes comes with an additional burden of moderate to severe hyperlipidemia, but little is known about the effects of lipid-lowering therapy on diabetic complications such as diabetes-associated cognitive decline. Herein we investigated the effects of statins on memory impairment and neurotoxicity in streptozotocin-induced diabetic mice. Our data indicated that oral administration of simvastatin at 10 or 20mg/kg for 4weeks significantly ameliorated diabetes-associated memory impairment reflected by performance better in the Morris water maze and Y-maze tests. The further study showed that these treatments caused significant increase of peroxisome proliferator-activated receptors gamma and decrease of NF-κB p65 in nucleus of hippocampus and cortex, and ameliorated neuroinflammatory response as evidenced by less Iba-1-positive cells and lower inflammatory mediators including IL-1β, IL-6 and TNF-α as well as suppressed neuronal apoptosis as indicated by decreased TUNEL-positive cells, increased ratio of Bcl-2/Bax and decreased caspase-3 activity in the hippocampus and cortex. Moreover, simvastatin pronouncedly attenuated amyloidogenesis by decreasing amyloid-β, amyloid precursor protein (APP) and beta-site APP cleaving enzyme-1. As expected, treated with simvastatin, the diabetic mice exhibited significant improvement of hyperlipidemia rather than hyperglycemia. Our findings disclosed novel therapeutic potential of simvastatin for the diabetes-associated cognitive impairment.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Blood Glucose; Brain; Cytokines; Diabetes Mellitus, Experimental; Disease Models, Animal; Hypolipidemic Agents; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred ICR; Neurotoxicity Syndromes; Peptide Fragments; Signal Transduction; Simvastatin

The study determined the effect of thymoquinone rich fraction (TQRF) and thymoquinone (TQ) in the forms of nano- and conventional emulsions on learning and memory, lipid peroxidation, total antioxidant status, antioxidants genes expression and soluble β-amyloid (Aβ) levels in rats fed with a high fat-cholesterol diet (HFCD). The TQRF was extracted from Nigella sativa seeds using a supercritical fluid extraction system and prepared into nanoemulsion, which later named as TQRF nanoemulsion (TQRFNE). Meanwhile, TQ was acquired commercially and prepared into thymoquinone nanoemulsion (TQNE). The TQRF and TQ conventional emulsions (CE), named as TQRFCE and TQCE, respectively were studied for comparison. Statin (simvastatin) and non-statin (probucol) cholesterol-lowering agents, and a mild-to-severe Alzheimer's disease drug (donepezil) were served as control drugs. The Sprague Dawley rats were fed with HFCD for 6 months, and treated with the intervention groups via oral gavage daily for the last 3 months. As a result, HFCD-fed rats exhibited hypercholesterolaemia, accompanied by memory deficit, increment of lipid peroxidation and soluble Aβ levels, decrement of total antioxidant status and down-regulation of antioxidants genes expression levels. TQRFNE demonstrated comparable effects to the other intervention groups and control drugs in serum biomarkers as well as in the learning and memory test. Somehow, TQRFNE was more prominent than those intervention groups and control drugs in brain biomarkers concomitant to gene and protein expression levels. Supplementation of TQRFNE into an HFCD thus could ameliorate memory deficit, lipid peroxidation and soluble Aβ levels as well as improving the total antioxidant status and antioxidants genes expression levels.

Topics: Amyloid beta-Peptides; Animals; Antioxidants; Benzoquinones; Blood Glucose; Body Weight; Brain; Diet, High-Fat; Emulsions; Gene Expression Regulation; Lipid Peroxidation; Lipids; Male; Memory Disorders; Nanoparticles; Nigella sativa; Oxidoreductases; Peptide Fragments; Rats; Rats, Sprague-Dawley

Cocaine- and amphetamine-regulated transcript (CART) peptide has been demonstrated to exert neuroprotective effects in stroke and some neurodegeneration diseases. In current study, we investigated the protective effects and underlying mechanisms of CART in APP/PS1 mice.. CART decreases the levels of soluble Aβ in the hippocampus of APP/PS1 mice by modulating the expression of Aβ metabolism-associated enzymes, which may be associated with the MAPK and AKT pathways.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cells, Cultured; Disease Models, Animal; Hippocampus; Humans; Male; Maze Learning; Memory Disorders; Mice, Transgenic; Nerve Tissue Proteins; Neuroprotective Agents; Nootropic Agents; Peptide Fragments; Presenilin-1; Random Allocation; Spatial Memory

Diffusion imaging has demonstrated sensitivity to structural brain changes in Alzheimer's disease (AD). However, there remains a need for a more complete characterization of microstructural alterations occurring at the earliest disease stages, and how these changes relate to underlying neuropathology. This study evaluated the sensitivity of restriction spectrum imaging (RSI), an advanced diffusion magnetic resonance imaging (MRI) technique, to microstructural brain changes in mild cognitive impairment (MCI) and AD.. MRI and neuropsychological test data were acquired from 31 healthy controls, 12 individuals with MCI, and 13 individuals with mild AD, aged 63-93 years. Cerebrospinal fluid amyloid-β levels were measured in a subset (n = 38) of participants. RSI measures of neurite density (ND) and isotropic free water (IF) were computed in fiber tracts and in hippocampal and entorhinal cortex gray matter, respectively. Analyses evaluated whether these measures predicted memory performance, correlated with amyloid-β levels, and distinguished impaired individuals from controls. For comparison, analyses were repeated with standard diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA) and mean diffusivity.. Both RSI and DTI measures correlated with episodic memory and disease severity. RSI, but not DTI, measures correlated with amyloid-β42 levels. ND and FA in the arcuate fasciculus and entorhinal cortex IF most strongly predicted recall performance. RSI measures of arcuate fasciculus ND and entorhinal cortex IF best discriminated memory impaired participants from healthy participants.. RSI is highly sensitive to microstructural changes in the early stages of AD, and is associated with biochemical markers of AD pathology. Reduced ND in cortical association fibers and increased medial temporal lobe free-water diffusion predicted episodic memory, distinguished cognitively impaired from healthy individuals, and correlated with amyloid-β. Although further research is needed to assess the sensitivity of RSI to preclinical AD and disease progression, these results suggest that RSI may be a promising tool to better understand neuroanatomical changes in AD and their association with neuropathology.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Anisotropy; Brain; Diffusion Tensor Imaging; Female; Humans; Image Processing, Computer-Assisted; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Peptide Fragments; Psychiatric Status Rating Scales

Amyloid-β (Aβ) aggregation is thought to be a major pathogenic event underlying the neuropathology of Alzheimer's disease (AD). The development of new drugs inhibiting the Aβ aggregation process is, therefore, important. SEN1500, an orally bioavailable and CNS-penetrant Aβ aggregation inhibitor, has previously been shown to reduce spatial learning and memory deficits in an APP transgenic mouse model. To verify that the pharmacological properties of SEN1500 are not unique to this model, we investigated brain Aβ pathology, neuroinflammation, as well as memory in a different mouse model of AD expressing the human amyloid precursor protein with Swedish and London mutations (APP. APP. SEN1500 treatment lowered insoluble Aβ levels and β-amyloid plaque load in the brain compared with control-treated APP. SEN1500 is not only able to reduce Aβ pathology and activated microglia but also to improve learning and memory as previously shown, making SEN1500 a potential candidate for human AD treatment. This Aβ aggregation inhibitor could be a promising therapeutic agent for the disease-modifying treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Brain; Cerebral Cortex; Disease Models, Animal; Encephalitis; Hippocampus; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Peptide Fragments; Plaque, Amyloid; Pyrimidines; Spatial Learning

Alzheimer's disease (AD) is a progressive degenerative condition. In order to treat AD, the use of a "drug repositioning" or "repurposing" approach with potential disease-modifying compounds has been increased. The new generation antipsychotics are commonly used in AD and other dementias for the treatment of psychosis and behavioral symptoms, and several animal models have shown the effects of these potential disease-modifying compounds. In this study, we examined whether long-term clozapine treatment could reduce amyloid beta (Aβ) deposition and cognitive impairment in transgenic mice of AD, Tg-APPswe/PS1dE9. AD mice were fed clozapine at 20 mg/kg/day for 3 months from 4.5 months of age. Intake of clozapine improved the Aβ-induced memory impairment and suppressed Aβ levels and plaque deposition in the brain of AD mice. Clozapine upregulated Trk, brain-derived neurotrophic factor, cyclin-dependent kinase-5, and p35 in the cortex and hippocampus of AD mice and activated AMP-activated protein kinase (AMPK). As a downstream effector of AMPK, beta-secretase expression was decreased by clozapine administration. Moreover, clozapine-phosphorylated synapsin I at Ser9 and Ser549 sites in the hippocampus and cortex of AD mice, which may be involved in synaptic strength. This study suggests that as one of candidate for multi-target approach of AD treatment, clozapine is proposed as a therapeutic drug for treatment of AD patients.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Clozapine; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Presenilin-1

Alzheimer's disease (AD) is characterized with progressive memory loss and severe cognitive impairments, which affect everyday life and human health in the elderly. It is required that an effective and safe protective reagent against AD should be developed. It has been reported that humanin (HN) exerts neuroprotective effects against AD. In this study, we investigated the effect of a novel and more effective HN derivative, Colivelin (CLN) on AD.. PDAPP(V717I) transgenic AD model mice (derived from parental C57/BL6 mice) were used in our study as AD model. Morris water maze test was used to test the memory impairment of AD mice and the levels of Aβ40 and Aβ42 were determined by an Elisa assay. We used an Immunohistochemistry and Immunofluorescence staining method to check the GFAP and MAP2 positive cells, and TUNEL to assess the apoptotic cells. Western blot assay was used to check the expression and phosphorylation level of p38.. We found that CLN improved the memory impairment induced by AD and reduced the deposit of Aβ40 and Aβ42. CLN also inhibited cell apoptosis and activation of caspase 3 in brain tissues of AD mice. Inflammation in AD mice was alleviated by CLN treatment, including the accumulation of GFAP positive cells and the inflammatory cytokines. With both structure of AGA-HNG and ANDF, CLN exhibited significantly stronger effects than synchronously administration of AGA-HNG and ADNF, suggesting CLN as a novel potential effective therapeutic reagent for AD patients. Finally, we found that CLN inhibited phosphorylation of p38 in AD mice and p38 inhibitor, SB203580 weakened the therapeutic effect of CLN.. CLN effectively improved the memory dysfunction in PDAPP mice, and our data suggests CLN as a novel and effective reagent which may have great potentials in AD therapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Disease Models, Animal; Gene Expression Regulation; Humans; Intracellular Signaling Peptides and Proteins; Memory; Memory Disorders; Mice; Mice, Transgenic; Neuroprotective Agents; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Phosphorylation

We previously reported the production of transgenic rats (APP21 line) that over-express human amyloid precursor protein (APP) containing Swedish and Indiana mutations. In order to generate a better model for Alzheimer's disease (AD), the APP21 rat line was used to generate double transgenic line that over-expressed Presenilin 1 (PS1) with L166P mutation in addition to APP transgene (APP + PS1 line).. Thirty-two double transgenic founders were generated and the ultimate transgenic founder was selected based on PS1 transgene copy number and level of amyloid-beta (Aβ)42 peptide. The APP + PS1 double transgenic rats had 38 times more PS1 in brains compared to APP rats. Behavioral assessment using Barnes maze showed that APP + PS1 rats exhibited a larger learning and memory deficit than APP21 rats. Double transgenic rats also produced more Aβ42. Histological examination of the brains showed that the APP21 rat line displayed neurofibrillary tangles and in contrast, the APP + PS1 line showed chromatolysis in hippocampal neurons and neuronal loss in CA3 region of hippocampus.. Due to the separate segregation of APP and PS1 transgenes in APP + PS1 double transgenic rats, this transgenic line may be a valuable model for studying the effects of various levels of APP and PS1 transgenes on various aspects of brain pathologies associated with the AD phenotype.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Disease Models, Animal; Female; Humans; Maze Learning; Memory Disorders; Mutation; Neurofibrillary Tangles; Neurons; Peptide Fragments; Presenilin-1; Rats, Inbred F344; Rats, Sprague-Dawley; Rats, Transgenic; RNA, Messenger

Aftins (amyloid forty-two inducers) represent a novel class of tri-substituted purines derived from roscovitine, able to promote the generation of amyloid-β (Aβ)1-42 from amyloid-β protein precursor through γ-secretase activation in cell cultures. We here examined whether aftin-4 could provoke an amyloid-like toxicity in vivo in mice. The intracerebroventricular administration of aftin-4 (3-20 nmol) increased Aβ1-42, but not Aβ1-40, content in the mouse hippocampus, between 5 and 14 days after injection. Aftin-4 injection increased lipid peroxidation levels in the hippocampus, an index of oxidative stress. It increased brain contents in pro-inflammatory cytokines, IL-1β, IL-6, and TNFα, and GFAP immunolabeling, showing astrocytic reaction. Expression of the synaptic marker synaptophysin was decreased by aftin-4. Finally, the treatment provoked marked learning deficits, observed using different memory procedures: Spontaneous alternation in the Y-maze, place learning in the water-maze, and passive avoidance response. The systemic intraperitoneal injection of aftin-4 in the 3-30 mg/kg dose range also induced oxidative stress and learning deficits. All these alterations could be blocked by pre-treatment with the γ-secretase inhibitor BMS-299,897, confirming that the mechanism of action of aftin-4 involves secretase activity. Furthermore, we examined if the cholinesterase inhibitor donepezil and the non-steroidal anti-inflammatory drug ibuprofen could prevent aftin-4-induced memory impairments, cytokine release, and lipid peroxidation. Donepezil prevented all alterations, whereas ibuprofen prevented the increases in cytokine release and lipid peroxidation, but only marginally the memory impairments. As a whole, this study showed that in vivo injection of aftin-4 results in a rapid, acute Alzheimer's disease-like toxicity in the rodent brain.

Topics: Adenine; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Butyrates; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Encephalitis; Enzyme Inhibitors; Hippocampus; Hydrocarbons, Halogenated; Ibuprofen; Indans; Learning Disabilities; Male; Memory Disorders; Mice; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Piperidines

Donepezil, a cholinesterase inhibitor, is a representative symptomatic therapy for Alzheimer's disease (AD). Recent studies have reported the anti-inflammatory effects of donepezil. However, limited studies that investigate its anti-inflammatory effect in AD have been reported. Considering the role of proinflammatory molecules and microglial activation in the pathogenesis of AD, the current study aimed to elucidate the effects of donepezil on microglial activation induced by amyloid deposition in transgenic mice. Our results showed that chronic treatment with donepezil significantly improved the cognitive function in the novel object recognition test and Morris water maze test in amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice. We further demonstrated that these cognitive enhancements were related to the anti-inflammatory effect of donepezil. We found that donepezil could inhibit the expression of CD68, a specific marker of microglial activation, and reduce the release of proinflammatory cytokines including tumor necrosis factor-α and interleukin-1β. Immunohistochemistry and Congo red co-staining revealed that congophilic amyloid and activated microglia around plaques were also reduced by donepezil treatment. Enzyme-linked immunosorbent assay (ELISA) analysis showed that donepezil decreased insoluble Aβ40/Aβ42 and soluble Aβ40 levels. Moreover, donepezil reversed the impaired expression of insulin-degrading enzyme in the hippocampus of APP/PS1 mice. Our findings indicated that donepezil improves cognitive deficits in APP/PS1 mice by a mechanism that may be associated with its inhibition of microglial activation and release of proinflammatory cytokines.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Brain; Cytokines; Donepezil; Indans; Learning Disabilities; Male; Maze Learning; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Neurites; Nootropic Agents; Peptide Fragments; Piperidines; Plaque, Amyloid; Presenilin-1; Random Allocation; Recognition, Psychology

Neuroprotection of erythropoietin (EPO) following long-term administration is hampered by the associated undesirable effects on hematopoiesis and body weight. For this reason, we tested carbamylated-EPO (CEPO), which has no effect on erythropoiesis, and compared it with EPO in the AβPP/PS1 mouse model of familial Alzheimer’s disease. Groups of 5-month old wild type (WT) and transgenic mice received chronic treatment consisting of CEPO (2,500 or 5,000 UI/kg) or EPO (2,500 U I/kg) 3 days/week for 4 weeks. Memory at the end of treatment was assessed with the object recognition test. Microarray analysis and quantitative-PCR were used for gene expression studies. No alterations in erythropoiesis were observed in CEPO-treated WT and AβPP/PS1 transgenic mice. EPO and CEPO improved memory in AβPP/PS1 animals. However, only EPO decreased amyloid-β (Aβ)plaque burden and soluble Aβ(40). Microarray analysis of gene expression revealed a limited number of common genes modulated by EPO and CEPO. CEPO but not EPO significantly increased gene expression of dopamine receptors 1 and 2, and adenosine receptor 2a, and significantly down-regulated adrenergic receptor 1D and gastrin releasing peptide. CEPO treatment resulted in higher protein levels of dopamine receptors 1 and 2 in WT and AβPP/PS1 animals, whereas the adenosine receptor 2a was reduced in WT animals. The present results suggest that the improved behavior observed in AβPP/PS1 transgenic mice after CEPO treatment may be mediated, at least in part, by the observed modulation of the expression of molecules involved in neurotransmission.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Body Weight; Disease Models, Animal; Erythropoietin; Gastrin-Releasing Peptide; Gene Expression Regulation; Humans; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Peptide Fragments; Presenilin-1; Receptors, Catecholamine; Synapses; Time Factors

Electroconvulsive therapy (ECT) is an effective treatment for depression, but can result in memory deficits. This study aimed to determine whether ketamine could alleviate electroconvulsive shock (ECS, an analog of ECT in animals)-induced memory impairment and the potential molecular mechanism. Chronic unpredictable mild stress was used to generate animal models of depressive-like symptoms. Sixty adult male Sprague-Dawley rats were randomly divided into the following five groups: control group (group C); depressive-like model group (group D); ECS group (group DE); ketamine+ECS group (group DKE); and ketamine group (group DK). The sucrose preference test and Morris water maze were used to assess behavioral changes. The expression levels of Iba-1, IL-1β and TNF-α were measured by immunohistochemistry and real-time PCR. Enzyme-linked immunosorbent assays were used to detect the levels of soluble Aβ. We found that ECS up-regulated the expression of Iba-1, promoted the release of IL-1β and TNF-α, increased the levels of Aβ1-40 and Aβ1-42 in the hippocampus, and aggravated memory impairment of the depressive-like rats. However, ketamine reversed these ECS-induced molecular changes and effectively attenuated ECS-induced memory impairment. This cognitive protective effect of ketamine may be attributed to its suppression of ECS-induced neuroinflammation and reduction of the levels of soluble Aβ.

Topics: Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Calcium-Binding Proteins; Depression; Electroshock; Hippocampus; Inflammation; Interleukin-1beta; Ketamine; Male; Maze Learning; Memory Disorders; Microfilament Proteins; Peptide Fragments; Rats, Sprague-Dawley; RNA, Messenger; Solubility; Tumor Necrosis Factor-alpha

Alzheimer's disease (AD) is a major cause of dementia in the elderly. Although early-onset (familial) AD is attributed to gene mutations, the cause for late-onset (sporadic) AD, which accounts for 95% of AD cases, is unknown. In this study, we show that exposure of 6-week-old amyloid beta precursor protein (APP)/presenilin (PS1) overexpressing mice, a well-established animal model of AD, and nontransgenic littermates to a cyclic O3 exposure protocol, which mimics environmental exposure episodes, accelerated learning/memory function loss in male APP/PS1 mice but not in female APP/PS1 mice or nontransgenic littermates. Female APP/PS1 mice had higher brain levels of amyloid beta peptide (Aβ42) and Aβ40, compared with male APP/PS1 mice; O3 exposure, however, had no significant effect on brain Aβ load in either male or female mice. Our results further show that male APP/PS1 mice had lower levels of antioxidants (glutathione and ascorbate) and experienced augmented induction of NADPH oxidases, lipid peroxidation, and neuronal apoptosis upon O3 exposure, compared with female APP/PS1 mice. No significant effect of O3 on any of these parameters was detected in nontransgenic littermates. In vitro studies further show that 4-hydroxynonenal, a lipid peroxidation product which was increased in the plasma and cortex/hippocampus of O3-exposed male APP/PS1 mice, induced neuroblastoma cell apoptosis. Together, the results suggest that O3 exposure per se may not cause AD but can synergize with genetic risk factors to accelerate the pathophysiology of AD in genetically predisposed populations. The results also suggest that males may be more sensitive to O3-induced neuropathophysiology than females due to lower levels of antioxidants.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Apoptosis; Brain Chemistry; Female; Lipid Peroxidation; Male; Memory Disorders; Mice; NADPH Oxidases; Nervous System Diseases; Neurons; Ozone; Peptide Fragments; Presenilins; Sex Characteristics

Gintonin is a novel ginseng-derived lysophosphatidic acid (LPA) receptor ligand. Oral administration of gintonin ameliorates learning and memory dysfunctions in Alzheimer's disease (AD) animal models. The brain cholinergic system plays a key role in cognitive functions. The brains of AD patients show a reduction in acetylcholine concentration caused by cholinergic system impairments. However, little is known about the role of LPA in the cholinergic system. In this study, we used gintonin to investigate the effect of LPA receptor activation on the cholinergic system in vitro and in vivo using wild-type and AD animal models. Gintonin induced [Ca(2+)]i transient in cultured mouse hippocampal neural progenitor cells (NPCs). Gintonin-mediated [Ca(2+)]i transients were linked to stimulation of acetylcholine release through LPA receptor activation. Oral administration of gintonin-enriched fraction (25, 50, or 100 mg/kg, 3 weeks) significantly attenuated scopolamine-induced memory impairment. Oral administration of gintonin (25 or 50 mg/kg, 2 weeks) also significantly attenuated amyloid-β protein (Aβ)-induced cholinergic dysfunctions, such as decreased acetylcholine concentration, decreased choline acetyltransferase (ChAT) activity and immunoreactivity, and increased acetylcholine esterase (AChE) activity. In a transgenic AD mouse model, long-term oral administration of gintonin (25 or 50 mg/kg, 3 months) also attenuated AD-related cholinergic impairments. In this study, we showed that activation of G protein-coupled LPA receptors by gintonin is coupled to the regulation of cholinergic functions. Furthermore, this study showed that gintonin could be a novel agent for the restoration of cholinergic system damages due to Aβ and could be utilized for AD prevention or therapy.

Topics: Acetylcholine; Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Animals; Calcium Signaling; Cells, Cultured; Choline O-Acetyltransferase; Cholinergic Neurons; Disease Models, Animal; Hippocampus; Male; Memory Disorders; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Transgenic; Neural Stem Cells; Peptide Fragments; Plant Extracts; Scopolamine

Aging is the most important risk factor associated with Alzheimer's disease (AD); however, the molecular mechanisms linking aging to AD remain unclear. Suppression of the ribosomal protein S6 kinase 1 (S6K1) increases healthspan and lifespan in several organisms, from nematodes to mammals. Here we show that S6K1 expression is upregulated in the brains of AD patients. Using a mouse model of AD, we found that genetic reduction of S6K1 improved synaptic plasticity and spatial memory deficits, and reduced the accumulation of amyloid-β and tau, the two neuropathological hallmarks of AD. Mechanistically, these changes were linked to reduced translation of tau and the β-site amyloid precursor protein cleaving enzyme 1, a key enzyme in the generation of amyloid-β. Our results implicate S6K1 dysregulation as a previously unidentified molecular mechanism underlying synaptic and memory deficits in AD. These findings further suggest that therapeutic manipulation of S6K1 could be a valid approach to mitigate AD pathology.. Aging is the most important risk factor for Alzheimer's disease (AD). However, little is known about how it contributes to AD pathogenesis. S6 kinase 1 (S6K1) is a protein kinase involved in regulation of protein translation. Reducing S6K1 activity increases lifespan and healthspan. We report the novel finding that reducing S6K1 activity in 3xTg-AD mice ameliorates synaptic and cognitive deficits. These improvement were associated with a reduction in amyloid-β and tau pathology. Mechanistically, lowering S6K1 levels reduced translation of β-site amyloid precursor protein cleaving enzyme 1 and tau, two key proteins involved in AD pathogenesis. These data suggest that S6K1 may represent a molecular link between aging and AD. Given that aging is the most important risk factor for most neurodegenerative diseases, our results may have far-reaching implications into other diseases.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Humans; Locomotion; Long-Term Potentiation; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Neuronal Plasticity; Neurons; Peptide Fragments; Presenilin-1; Proteasome Endopeptidase Complex; Ribosomal Protein S6 Kinases, 90-kDa; Signal Transduction; tau Proteins

Fibrillar aggregates of β-amyloid protein (Aβ) are the main constituent of senile plaques and considered to be one of the causative events in the pathogenesis of Alzheimer's disease (AD). Compounds that could inhibit Aβ fibrils formation, disaggregate preformed Aβ fibrils as well as reduce their associated neurotoxicity might have therapeutic values for treating AD. In this study, the inhibitory effects of bis (heptyl)-cognitin (B7C), a multifunctional dimer derived from tacrine, on aggregation and neurotoxicity of Aβ1-40 were evaluated both in vitro and in vivo.. Thioflavin T fluorescence assay was carried out to evaluate Aβ aggregation, MTT and Hoechst-staining assays were performed to investigate Aβ-associated neurotoxicity. Fluorescent probe DCFH-DA was used to estimate the accumulation of intracellular reactive oxygen stress (ROS). Morris water maze was applied to determine learning and memory deficits induced by intracerebroventricular infusion of Aβ in rats.. B7C (0.1-10 μM), but not tacrine, effectively inhibited Aβ fibrils formation and disaggregated preformed Aβ fibrils following co-incubation of B7C and Aβ monomers or preformed fibrils, respectively. In addition, B7C markedly reduced Aβ fibrils-associated neurotoxicity in SH-SY5Y cell line, as evidenced by the increase in cell survival, the decrease in Hoechst-stained nuclei and in intracellular ROS. Most encouragingly, B7C (0.1 and 0.2 mg/kg), 10 times more potently than tacrine (1 and 2 mg/kg), inhibited memory impairments after intracerebroventricular infusion of Aβ in rats, as evidenced by the decrease in escape latency and the increase in the spatial bias in Morris water maze test along with upregulation of choline acetyltransferase activity and downregulation of acetylcholinesterase activity.. These findings provide not only novel molecular insight into the potential application of B7C in treating AD, but also an effective approach for screening anti-AD agents.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Male; Maze Learning; Memory Disorders; Neuroprotective Agents; Peptide Fragments; Rats, Sprague-Dawley; Reactive Oxygen Species; Tacrine

Klotho, an aging-suppressor gene, encodes a protein that potentially acts as a neuroprotective factor by modulating insulin-like growth factor 1 signaling and oxidative stress. In the present study, we investigated the potential role of Klotho in the therapeutic effect of ligustilide against Alzheimer's disease (AD)-like neuropathologies and memory impairment in aged senescence-accelerated mouse prone-8 (SAMP8) mice. Ligustilide treatment (10 and 40 mg/kg for 8 weeks, intragastrically) in 10-month-old SAMP8 mice reduced memory deficits, amyloid-β(1)-42 accumulation, tau phosphorylation, and neuron loss, increased mitochondrial manganese-superoxide dismutase and catalase expression and activity, and decreased malondialdehyde, protein carbonyl, and 8-hydroxydesoxyguanosine levels in the brain. Ligustilide upregulated Klotho expression in the cerebral choroid plexus and serum, decreased Akt and Forkhead box class O1 phosphorylation. Moreover, ligustilide inhibited the insulin-like growth factor 1 pathway and induced Forkhead box class O1 activation in 293T cells along with Klotho upregulation. An inverse correlation was found between Klotho expression and the AD phenotype, suggesting that Klotho might be a novel therapeutic target for age-related AD, and Klotho upregulation might contribute to the neuroprotective effect of ligustilide against AD.

Topics: 4-Butyrolactone; Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cells, Cultured; Disease Models, Animal; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression Regulation, Developmental; Glucuronidase; Insulin-Like Growth Factor I; Klotho Proteins; Male; Memory Disorders; Mice; Mice, Inbred Strains; Molecular Targeted Therapy; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Phosphorylation; Signal Transduction; tau Proteins; Up-Regulation

In the context of Alzheimer's disease (AD), hippocampal alterations have been well described in advanced stages of the pathology, when amyloid deposition, inflammation and glial activation occur, but less attention has been directed to studying early brain and behavioral changes. Using an animal model of AD, the transgenic PDAPP-J20 mouse at 5 months of age, when no amyloid plaques are present and low cerebral levels of amyloid peptides are detectable, we found structural, morphological, and cellular alterations in the hippocampus. Young transgenic mice showed a reduced hippocampal volume with less number of pyramidal and granular neurons, which additionally exhibited cell atrophy. The neurogenic capability in this zone, measured as DCX+ cells, was strongly diminished and associated to alterations in cell maturity. A decrease in presynaptic synaptophysin optical density was detected in mossy fibers reaching CA3 subfield but not in Golgi stained- CA1 dendritic spine density. Employing confocal microscopy and accurate stereological tools we also found a reduction in the number of GFAP+ cells, along with decreased astrocyte complexity, suggesting a potential detriment of neural support. According with untimely neuroglial alterations, young PDAPP mice failed in the novel location recognition test, that depends on hippocampal function. Moreover, multivariate statistical analysis of the behavioral outcome in the open-field test evidenced an elevated anxiety score in Tg mice compared with age-matched control mice. In line with this, the transgenic group showed a higher number of c-Fos+ nuclei in central and basolateral amygdala, a result that supports the early involvement of the emotionality factor in AD pathology. Applying an integrative approach, this work focuses on early structural, morphological and functional changes and provides new and compelling evidence of behavioral alterations that precede manifest AD.

Topics: Alzheimer Disease; Amygdala; Amyloid; Amyloid beta-Peptides; Animals; Anxiety; Astrocytes; Atrophy; Disease Models, Animal; Disease Progression; Doublecortin Protein; Exploratory Behavior; Hippocampus; Humans; Memory Disorders; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Peptide Fragments; Plaque, Amyloid; Proto-Oncogene Proteins c-fos; Recombinant Fusion Proteins; Spatial Behavior; Synaptophysin

Amyloid oligomers have a critical function in the pathologic processes of various amyloidoses, such as Alzheimer's disease (AD), Parkinson disease (PD), Huntington's disease, prion-related diseases, type 2 diabetes, and hereditary renal amyloidosis. Our previous reports demonstrated that a conformation-dependent oligomer-specific single-chain variable fragment (scFv) antibody, W20, isolated from a naïve human scFv library, can recognize oligomers assembled from α-synuclein, amylin, insulin, Aβ40/42, prion peptide 106-126, and lysozyme, inhibit the aggregation of various amyloid, and attenuate amyloid oligomer-induced cytotoxicity In vitro. Furthermore, W20 recognized the amyloid oligomers in all types of plaques, Lewy bodies, and amylin deposits in the brain tissues of AD and PD patients and in the pancreas of type 2 diabetes patients. In the current study, we showed that W20 blocked the binding of Aβ oligomers to SH-SY5Y cells, did not bind to heat shock protein, rescued cognitive impairments in APP/PS1 transgenic mice, and interfered with Aβ levels and deposits in mouse brain. These results suggest that W20 may be a promising therapeutic for the treatment of AD.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cell Line, Tumor; Cell Membrane; Female; Heat-Shock Proteins; Humans; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Plaque, Amyloid; Presenilin-1; Single-Chain Antibodies

Preclinical and post-mortem studies suggest that Alzheimer disease (AD) causes cerebrovascular dysfunction, and therefore may enhance susceptibility to cerebrovascular disease (CVD). The objective of this study was to investigate this association in a memory clinic population.. The AD biomarkers CSF amyloid β42, amyloid β40 and APOE-ε4 status have all been linked to increased CVD risk in AD, and therefore the first aim of this study was to analyze the association between these biomarkers and CVD. In 92 memory clinic patients the cross-sectional association between AD biomarkersand the severity of CVD was investigated with linear regression analysis. Additionally, we studied whether AD biomarkers modified the relation between vascular risk factors and CVD. CVD was assessed on MRI through a visual rating scale.Analyses were adjusted for age. The second aim of this study was to investigate the association between clinical AD and CVD, where 'clinical AD' was defined as follows: impairment in episodic memory, hippocampal atrophy and an aberrant concentration of cerebrospinal fluid (CSF) biomarkers. 47 of the 92 patients had AD.. No association between CSF amyloid β42, amyloid β40 or APOE-ε4 status and CVD severity was found, nor did these AD biomarkers modify the relation between vascular risk factors and CVD. Clinical AD was not associated with CVD severity (p=0.83). Patients with more vascular risk factors had more CVD, but this relationship was not convincingly modified by AD (p=0.06).. In this memory clinic population, CVD in patients with AD was related to vascular risk factors and age, comparable to patients without AD. Therefore, in our study, the preclinical and post-mortem evidence that AD would predispose to CVD could not be translated clinically. Further work, including replication of this work in a different and larger sample, is warranted.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Brain; Cerebrovascular Disorders; Female; Humans; Linear Models; Magnetic Resonance Imaging; Male; Memory Disorders; Peptide Fragments; Risk Factors; Severity of Illness Index

Familial hypercholesterolemia is caused by inherited genetic abnormalities that directly or indirectly affect the function of the low-density lipoprotein (LDL) receptor. This condition is characterized by defective catabolism of LDL which results in increased plasma cholesterol concentrations and premature coronary artery disease. Nevertheless, there is increasing preclinical and clinical evidence indicating that familial hypercholesterolemia subjects show a particularly high incidence of mild cognitive impairment. Moreover, the LDL receptor (LDLr) has been implicated as the main central nervous system apolipoprotein E receptor that regulates amyloid deposition in distinct mouse models of β-amyloidosis. In this regard, herein we hypothesized that the lack of LDLr would enhance the susceptibility to amyloid-β-(Aβ)-induced neurotoxicity in mice. Using the acute intracerebroventricular injection of aggregated Aβ(1-40) peptide (400 pmol/mouse), a useful approach for the investigation of molecular mechanisms involved in Aβ toxicity, we observed oxidative stress, neuroinflammation, and neuronal membrane damage within the hippocampus of C57BL/6 wild-type mice, which were associated with spatial reference memory and working memory impairments. In addition, our data show that LDLr knockout (LDLr(-/-)) mice, regardless of Aβ treatment, displayed memory deficits and increased blood-brain barrier permeability. Nonetheless, LDLr(-/-) mice treated with Aβ(1-40) peptide presented increased acetylcholinesterase activity, astrogliosis, oxidative imbalance, and cell permeability within the hippocampus in comparison with Aβ(1-40)-treated C57BL/6 wild-type mice. Overall, the present study shows that the lack of LDLr increases the susceptibility to Aβ-induced neurotoxicity in mice providing new evidence about the crosslink between familial hypercholesterolemia and cognitive impairment.

Topics: Acetylcholinesterase; Amyloid beta-Peptides; Amyloidosis; Animals; Antioxidants; Astrocytes; Blood-Brain Barrier; Capillary Permeability; Cell Membrane Permeability; Disease Models, Animal; Gliosis; Hippocampus; Memory Disorders; Memory, Short-Term; Mice, Inbred C57BL; Mice, Knockout; Neuroimmunomodulation; Oxidative Stress; Peptide Fragments; Prefrontal Cortex; Receptors, LDL; Spatial Memory; Superoxide Dismutase

Intravenous immunoglobulin (IVIg) is currently in clinical study for Alzheimer's disease (AD). However, preclinical investigations are required to better understand AD-relevant outcomes of IVIg treatment and develop replacement therapies in case of unsustainable supply.. We investigated the effects of IVIg in the 3xTg-AD mouse model, which reproduces both Aβ and tau pathologies. Mice were injected twice weekly with 1.5 g/kg IVIg for 1 or 3 months.. IVIg induced a modest but significant improvement in memory in the novel object recognition test and attenuated anxiety-like behavior in 3xTg-AD mice. We observed a correction of immunologic defects present in 3xTg-AD mice (-22% CD4/CD8 blood ratio; -17% IL-5/IL-10 ratio in the cortex) and a modulation of CX3CR1+ cell population (-13% in the bone marrow). IVIg treatment led to limited effects on tau pathology but resulted in a 22% reduction of the soluble Aβ42/Aβ40 ratio and a 60% decrease in concentrations of 56 kDa Aβ oligomers (Aβ*56).. The memory-enhancing effect of IVIg reported here suggests that Aβ oligomers, effector T cells and the fractalkine pathway are potential pharmacological targets of IVIg in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anxiety; Brain; CX3C Chemokine Receptor 1; Cytokines; Disease Models, Animal; Flow Cytometry; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Peptide Fragments; Presenilin-1; Receptors, Chemokine; tau Proteins

Transactive response DNA binding protein 43 (TDP-43) is detected in pathological inclusions in many cases of Alzheimer's disease (AD) and mild cognitive impairment (MCI), but its pathological role in AD and MCI remains unknown. Recently, TDP-43 was reported to contribute to pathogenesis in amyotrophic lateral sclerosis through its interaction with p65 nuclear factor κB (NF-κB) resulting in abnormal hyperactivation of this signaling pathway in motor neurons. Hence, we investigated the interaction of TDP-43 with p65 in the temporal cortex of subjects with a clinical diagnosis of MCI (n = 12) or AD (n = 12) as well as of age-matched controls with no cognitive impairment (NCI, n = 12).. Immunoprecipitation and immunofluorescence approaches revealed a robust interaction of TDP-43 with p65 in the nucleus of temporal lobe neurons in four individuals with MCI (named MCI-p). These MCI-p cases exhibited high expression levels of soluble TDP-43, p65, phosphorylated p65 and low expression levels of β-amyloid 40 when compared to AD or NCI cases. The analysis of cognitive performance tests showed that MCI-p individuals presented intermediate deficits of global cognition and episodic memory between those of AD cases and of NCI cases and MCI cases with no interaction of TDP-43 with p65.. From these results, we propose that enhanced NF-κB activation due to TDP-43 and p65 interaction may contribute to neuronal dysfunction in MCI individuals with episodic memory deficits. Accordingly, treatment with inhibitors of NF-κB activation may be considered for MCI individuals with episodic memory deficits.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; DNA-Binding Proteins; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoprecipitation; Longitudinal Studies; Male; Memory Disorders; Peptide Fragments; Statistics, Nonparametric; tau Proteins; Temporal Lobe; Transcription Factor RelA

Apolipoprotein E ε4 allele (ApoE4) has been associated with increased risk of sporadic Alzheimer's disease (AD) and of conversion from mild cognitive impairment to AD. But the underlying mechanism of ApoE4 affecting brain atrophy and cognition is not fully understood. We investigated the effect of ApoE4 on amyloid beta (Aβ) protein burden and its correlation with the structure change of hippocampus and cortex, cognitive and behavioral changes in ApoE4 transgenic mice. Male ApoE4 transgenic mice and age-matched control mice at age 12 months and 24 months were tested in the Morris Water Maze (MWM). Brain volume changes (including whole brain, hippocampus, cortex, total ventricles and caudate putamen) were assessed by using small animal 7T-MRI. Aβ level was assessed by immunohistochemistry (IHC) and immunoprecipitation/western blot. In MWM, escape latency was longer and time spent in the target quadrant was shorter in aged ApoE4 mice (12- and 24-month-old), suggesting age- and ApoE4-dependent visuospatial deficits. Atrophy on MRI was prominent in the hippocampus (p=0.039) and cortex (p=0.013) of ApoE4 mice (24-month-old) as compared to age-matched control mice. IHC revealed elevated Aβ deposition in the hippocampus. Consistently, both soluble and insoluble Aβ aggregates were increased in aged ApoE4 mice. This increase was correlated inversely with hippocampal atrophy and cognitive deficits. These data give further evidence that ApoE4 plays an important role in brain atrophy and memory impairment by modulating amyloid production and deposition.

Topics: Aging; Amyloid beta-Peptides; Animals; Apolipoprotein E4; Atrophy; Brain; Disease Models, Animal; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments; Polysomnography; Reaction Time; Statistics, Nonparametric; Time Factors

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

Tooth loss is a known risk factor of Alzheimer's disease (AD). However, the association of tooth loss with the molecular pathogenesis of AD is still unknown. The hypothesis that the molecular pathogenesis of AD is enhanced by molar tooth loss was tested. Seventeen female transgenic mice (J20) were divided into the experimental (EX, n=10) and control (C, n=7) groups. In the EX group, maxillary bilateral molar teeth were extracted at the age of 6 months. In the C group, however, these teeth remained intact. Passive avoidance test was performed to evaluate learning and memory abilities right after tooth extraction (6 months old) and 4 months later (10 months old). After the test at 10 months, amyloid beta (Aβ) deposition and changes of neuronal cell number and area in the hippocampus were investigated using half of the brains. The other half was homogenized and used to determine Aβ40 and Aβ42 levels by ELISA. At the 10 months of age, learning and memory abilities were significantly impaired in the EX group compared to the C group (P<0.05). The neuronal cell number in the CA1 and CA3 regions was significantly lower in the EX group than in the C group (P<0.05). Total Aβ, Aβ40, and Aβ42 levels showed no significant intergroup difference. Molar tooth loss may cause neuronal cell loss in the hippocampus, leading to memory impairment; this process may be independent of the amyloid cascade.

Topics: Adaptation, Ocular; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Avoidance Learning; Cell Death; Corticosterone; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Hippocampus; Humans; Memory Disorders; Mice; Mice, Transgenic; Mutation; Neurons; Peptide Fragments; Reaction Time; Time Factors; Tooth Loss

The abnormal accumulation of amyloid fibrils in the brain is pathognomonic of Alzheimer's disease. Amyloid fibrils induce significant neuroinflammation characterized by the activation of microglia and impairment of synaptic plasticity in the brain that eventually leads to cognitive decline. Chemokine fractalkine receptor (CX3CR1) is primarily located in the microglia in the brain and its role in the amyloid fibril-induced neuroinflammation and memory deficiency remains debated. We found that bilateral microinjection of amyloid beta (Aβ)1-40 fibrils into the hippocampal CA1 area of rats resulted in significant upregulation of CX3CR1 messenger RNA (mRNA) and protein expression (via increasing histone H3 acetylation in the Cx3cr1 promoter region), synaptic dysfunction, and cognitive impairment, compared with the control group. Suppressing CX3CR1 signaling with CX3CR1 small interfering RNA in rats injected with Aβ1-40 fibrils blunted Aβ1-40-induced CX3CR1 upregulation, microglial activation, interleukin-1β expression, restored basal glutamatergic strength and electric stimuli-induced long-term potentiation, and cognitive capacities. These findings suggest that activation of CX3CR1 plays an important role in the neuroinflammatory response and Aβ-induced neuroinflammation and neurotoxicity.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; CA1 Region, Hippocampal; CX3C Chemokine Receptor 1; Depression, Chemical; Disease Models, Animal; Gene Expression; Male; Memory Disorders; Microinjections; Neuronal Plasticity; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Chemokine; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Synapses; Up-Regulation

Our recent developments have yielded a novel phytoestrogenic formulation, referred to as the phyto-β-SERM formulation, which exhibits an 83-fold binding selectivity for the estrogen receptor subtype β (ERβ) over ERα. Earlier studies indicate that the phyto-β-SERM formulation is neuroprotective and promotes estrogenic mechanisms in the brain while devoid of feminizing activity in the periphery. Further investigation in a mouse model of human menopause indicates that chronic exposure to the phyto-β-SERM formulation at a clinically relevant dosage prevents/alleviates menopause-related climacteric symptoms. This study assessed the efficacy, in an early intervention paradigm, of the phyto-β-SERM formulation in the regulation of early stages of physical and neurological changes associated with Alzheimer's disease (AD) in a female triple transgenic mouse model of AD. Results demonstrated that, when initiated prior to the appearance of AD pathology, a 9-month dietary supplementation with the phyto-β-SERM formulation promoted physical health, prolonged survival, improved spatial recognition memory, and attenuated amyloid-β deposition and plaque formation in the brains of treated AD mice. In comparison, dietary supplementation of a commercial soy extract preparation showed no effect on cognitive measures, although it appeared to have a positive impact on amyloid pathology. In overall agreement with the behavioral and histological outcomes, results from a gene expression profiling analysis offered insights on the underlying molecular mechanisms associated with the two dietary treatments. In particular, the data suggests that there may be a crosstalk between ERβ and glycogen synthase kinase 3 signaling pathways that could play a role in conferring ERβ-mediated neuroprotection against AD. Taken together, these results support the therapeutic potential of the phyto-β-SERM formulation for prevention and/or early intervention of AD, and warrants further investigations in human studies.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Estrogen Receptor beta; Female; Humans; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Mutation; Ovariectomy; Peptide Fragments; Phytoestrogens; Plaque, Amyloid; Presenilin-1; Recognition, Psychology; tau Proteins

Deposition of β-amyloid (Aβ) as senile plaques and disrupted glucose metabolism are two main characteristics of Alzheimer's disease (AD). It is unknown, however, how these two processes are related in AD. Here we examined the relationship between O-GlcNAcylation, which is a glucose level-dependent post-translational modification that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to proteins, and Aβ production in a mouse model of AD carrying 5XFAD genes. We found that 1,2-dideoxy-2'-propyl-α-d-glucopyranoso-[2,1-D]-Δ2'-thiazoline (NButGT), a specific inhibitor of O-GlcNAcase, reduces Aβ production by lowering γ-secretase activity both in vitro and in vivo. We also found that O-GlcNAcylation takes place at the S708 residue of nicastrin, which is a component of γ-secretase. Moreover, NButGT attenuated the accumulation of Aβ, neuroinflammation, and memory impairment in the 5XFAD mice. This is the first study to show the relationship between Aβ generation and O-GlcNAcylation in vivo. These results suggest that O-GlcNAcylation may be a suitable therapeutic target for the treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; beta-N-Acetylhexosaminidases; Bridged Bicyclo Compounds, Heterocyclic; Conditioning, Psychological; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Fear; Gene Expression Regulation, Enzymologic; HEK293 Cells; Humans; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Mutation; Peptide Fragments; Plaque, Amyloid; Presenilin-1; Presenilin-2; Transfection

Neuropeptide Y (NPY) is a 36-amino acid peptide widely distributed in the central nervous system (CNS) that has been associated with the modulation of several functions including food intake, learning and memory, mood and neuroprotection. There is great interest in understanding the role of NPY in the deleterious effects induced by the central accumulation of amyloid-β (Aβ) peptides, a pathological hallmark of Alzheimer's disease (AD). Herein, we evaluated the effects of a single intracerebroventricular (i.c.v.) administration of NPY (0.0234 μmol/μL) 15 min prior to the i.c.v. injection of aggregated Aβ1-40 peptide (400 pmol/mouse) in behavioral and neurochemical parameters related to oxidative stress in mice. Pretreatment with NPY prevented Aβ1-40-induced depressive-like responses and spatial memory impairments evaluated in the tail suspension and object location tasks, respectively. The protective effects of NPY on spatial memory of Aβ1-40-treated mice were abolished by the pretreatment with the selective Y2 receptor antagonist BIIE0246. On the other hand, the administration of NPY and Aβ1-40 did not alter the performance of the animals in the elevated plus-maze and open field arena, indicating lack of effects on anxiety state and locomotor function. Although Aβ1-40 infusion did not change hippocampal and cortical glutathione peroxidase (GPx) activity and glutathione (GSH) levels, Aβ1-40-infused animals showed an increased lipid peroxidation in hippocampus and prefrontal cortex that were blunted by NPY administration. These findings indicate that central administration of NPY prevents Aβ1-40-induced depressive-like behavior and spatial memory deficits in mice and that this response is mediated, at least in part, by the activation of Y2 receptors and prevention of oxidative stress.

Topics: Amyloid beta-Peptides; Animals; Arginine; Benzazepines; Cerebral Cortex; Depression; Glutathione; Glutathione Peroxidase; Hippocampus; Injections, Intraventricular; Lipid Peroxidation; Male; Maze Learning; Memory Disorders; Mice; Motor Activity; Neuropeptide Y; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Receptors, Neuropeptide Y

Increasing evidence suggests that reductions in brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) may have a role in the pathogenesis of Alzheimer's disease (AD). However, the efficacy and safety profile of BDNF therapy (eg, gene delivery) remains to be established toward clinical trials. Here, we evaluated the effects of 7,8-dihydroxyflavone (7,8-DHF), a recently identified small-molecule TrkB agonist that can pass the blood-brain barrier, in the 5XFAD transgenic mouse model of AD. 5XFAD mice at 12-15 months of age and non-transgenic littermate controls received systemic administration of 7,8-DHF (5 mg/kg, i.p.) once daily for 10 consecutive days. We found that 7,8-DHF rescued memory deficits of 5XFAD mice in the spontaneous alternation Y-maze task. 5XFAD mice showed impairments in the hippocampal BDNF-TrkB pathway, as evidenced by significant reductions in BDNF, TrkB receptors, and phosphorylated TrkB. 7,8-DHF restored deficient TrkB signaling in 5XFAD mice without affecting endogenous BDNF levels. Meanwhile, 5XFAD mice exhibited elevations in the β-secretase enzyme (BACE1) that initiates amyloid-β (Aβ) generation, as observed in sporadic AD. Interestingly, 7,8-DHF blocked BACE1 elevations and lowered levels of the β-secretase-cleaved C-terminal fragment of amyloid precursor protein (C99), Aβ40, and Aβ42 in 5XFAD mouse brains. Furthermore, BACE1 expression was decreased by 7,8-DHF in wild-type mice, suggesting that BDNF-TrkB signaling is also important for downregulating baseline levels of BACE1. Together, our findings indicate that TrkB activation with systemic 7,8-DHF can ameliorate AD-associated memory deficits, which may be, at least in part, attributable to reductions in BACE1 expression and β-amyloidogenesis.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Brain; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Female; Flavones; Humans; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred Strains; Mice, Transgenic; Peptide Fragments; Phosphorylation; Receptor, trkB; Signal Transduction

Alzheimer's disease (AD) is an irreversible, progressive brain disorder of the elderly characterized by learning and memory impairment. Stress level glucocorticoids (GCs) and β-amyloid (Aβ) peptides deposition are found to be correlated with dementia progression in patients with AD. However, little is known about the simultaneous effects of glucocorticoids and Aβ on learning and memory impairment and its mechanism. In this study, 12-month-old male rats were chronically treated with Aβ(25-35) (10 μg/rat, hippocampal CA1 injection) and dexamethasone (DEX, 1.5mg/kg) for 14 days to investigate the effects of DEX and Aβ(25-35) treatment on learning and memory impairments, pathological changes, neuronal ultrastructure, amyloid precursor protein (APP) processing and neuronal cell apoptosis. Our results showed that DEX or Aβ(25-35) treatment alone for 14 days had caused slight damage on learning and memory impairments and hippocampal neurons, but damages were significantly increased with DEX+Aβ(25-35) treatment. And the mRNA levels of the APP, β-secretase and caspase 3 were significantly increased after DEX+Aβ(25-35) treatment. The immunohistochemistry demonstrated that APP, Aβ(1-40), caspase 3 and cytochrome c in hippocampus CA1 were significantly increased. Furthermore, Hoechst 33258 staining and Aβ(1-40) ELISA results showed that DEX+Aβ(25-35) treatment induced hippocampus CA1 neuron apoptosis and increased the level of Aβ(1-40). The results suggest that the simultaneous effects of GCs and Aβ may have important roles in the etiopathogenesis of AD, and demonstrate that stressful life events and GC therapy may increase the toxicity of Aβ and have cumulative impacts on the course of AD development and progression.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Apoptosis; Arabidopsis Proteins; Caspase 3; Cytochromes c; Dexamethasone; Disease Models, Animal; Drug Synergism; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Glucocorticoids; Hippocampus; Intramolecular Transferases; Learning Disabilities; Male; Maze Learning; Memory Disorders; Microscopy, Electron, Scanning; Neurons; Peptide Fragments; Rats; Rats, Sprague-Dawley; Time Factors

Long-term memory requires fine-tuning regulation of gene expression in specific neural circuits of the brain. Transcriptional regulation of gene programs is a key mechanism for memory storage and its deregulation may contribute to synaptic and cognitive dysfunction in memory disorders. The molecular mechanisms underlying changes on activity-dependent gene expression in Alzheimer's disease (AD) are largely unknown.. We analyzed the expression of activity-dependent genes regulated by the cAMP response element binding protein (CREB) and activation of CREB and its coactivator CREB-regulated transcription coactivator 1 (CRTC1) in control and mutant β-amyloid precursor protein (APP(Sw,Ind); Swedish and Indiana mutations) transgenic mice.. Gene expression analyses revealed specific downregulation of a subset of well-known activity-induced CREB-dependent genes, including c-fos, Bdnf and Nr4a2, in the hippocampus of memory-impaired APP(Sw,Ind) transgenic mice. Activity-dependent CREB transcription induced by calcium/cAMP signals is disrupted through a mechanism involving deregulation of calcium/calcineurin-mediated dephosphorylation and activation of CRTC1. Expression of CRTC1 and pharmacological activation of L-type voltage-gated calcium channels reverse the deficits in CRTC1-mediated transcription in APP(Sw,Ind) neurons.. Our results suggest that CRTC1 dysfunction caused by Aβ accumulation underlies changes in gene expression required for hippocampal-dependent memory in AD transgenic mice.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Calcineurin; Calcium; Cells, Cultured; Cerebral Cortex; Cyclic AMP; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Humans; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Mutation; Neurons; Peptide Fragments; Tetrodotoxin; Transcription Factors; Transfection

Growing evidence suggests that decreased brain-derived neurotrophic factor (BDNF) levels are associated with Alzheimer's disease (AD) pathogenesis. Therefore, BDNF gene therapy is considered to be a promising therapeutic strategy for treating AD. Sendai virus (SeV) is a type I parainfluenza virus that does not interact with host chromosomes because of its strict cytoplasmic life cycle. Although SeV is nonpathogenic in primates, including humans, its infectivity for neurons is strong. Here we demonstrate that SeV vectors effectively infected neurons, even though they were injected into subcortical white matter. Moreover, SeV vectors significantly induced BDNF expression, ameliorating synaptic degeneration and memory deficits in a transgenic mouse model of AD (Tg2576). This is the first study to demonstrate that viral vector administration in white matter is sufficient to restore cognitive function in vivo. These results also support the feasibility of using SeV vectors for gene therapy targeting the brain.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain-Derived Neurotrophic Factor; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Hippocampus; Humans; Male; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Nerve Degeneration; Neurons; Peptide Fragments; Sendai virus; Synapses

Alzheimer's disease (AD), the most common form of dementia, is characterized by memory deficits and deposition of amyloid-β (Aβ) in the brain. It has been known that neuroinflammation and oxidative stress are critical factors in the development of AD. 4-O-methylhonokiol, an extract from Magnolia officinalis, is known to have anti-inflammatory and anti-oxidative effects. Thus, we investigated the properties of 4-O-methylhonokiol against progression and development of AD in Tg2576 mice. Tg2576 mice models show memory impairment and AD-like pathological features including Aβ deposition. Oral administration of 4-O-methylhonokiol through drinking water (1 mg/kg in 0.0002% Tween 80) for 12 weeks not only prevented memory impairment but also inhibited Aβ deposition. In addition, 4-O-methylhonokiol decreased β-secretase activity, oxidative lipid and protein damage levels, activation of astrocytes and microglia cells, and generation of IL-1β and TNF-α with increase of glutathione level in the brain. Our results showed that 4-O-methylhonokiol effectively prevented memory impairment by down-regulating β-secretase activity through inhibition of oxidative stress and neuroinflammatory responses in Tg2576 transgenic mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Anti-Inflammatory Agents; Avoidance Learning; Biphenyl Compounds; Brain; Disease Models, Animal; Exploratory Behavior; Gene Expression Regulation; Glutathione; Humans; Lignans; Lipid Peroxidation; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Mutation; Oxidative Stress; Peptide Fragments; Protein Carbonylation; Time Factors

Therapeutic agents that improve the memory loss of Alzheimer's disease (AD) may eventually be developed if drug targets are identified that improve memory deficits in appropriate AD animal models. One such target is β-secretase which, in most AD patients, cleaves the wild-type (WT) β-secretase site sequence of the amyloid-β protein precursor (AβPP) to produce neurotoxic amyloid-β (Aβ). Thus, an animal model representing most AD patients for evaluating β-secretase effects on memory deficits is one that expresses human AβPP containing the WT β-secretase site sequence. BACE1 and cathepsin B (CatB) proteases have β-secretase activity, but gene knockout studies have not yet validated that the absence of these proteases improves memory deficits in such an animal model. This study assessed the effects of deleting these protease genes on memory deficits in the AD mouse model expressing human AβPP containing the WT β-secretase site sequence and the London γ-secretase site (AβPPWT/Lon mice). Knockout of the CatB gene in the AβPPWT/Lon mice improved memory deficits and altered the pattern of Aβ-related biomarkers in a manner consistent with CatB having WT β-secretase activity. But deletion of the BACE1 gene had no effect on these parameters in the AβPPWT/Lon mice. These data are the first to show that knockout of a putative β-secretase gene results in improved memory in an AD animal model expressing the WT β-secretase site sequence of AβPP, present in the majority of AD patients. CatB may be an effective drug target for improving memory deficits in most AD patients.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Aspartic Acid Endopeptidases; Brain; Cathepsin B; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Humans; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Peptide Fragments; Plaque, Amyloid; Reaction Time

Neuroinflammation is important in the pathogenesis and progression of Alzheimer disease (AD). Previously, we demonstrated that lipopolysaccharide (LPS)-induced neuroinflammation caused memory impairments. In the present study, we investigated the possible preventive effects of 4-O-methylhonokiol, a constituent of Magnolia officinalis, on memory deficiency caused by LPS, along with the underlying mechanisms.. We investigated whether 4-O-methylhonokiol (0.5 and 1 mg/kg in 0.05% ethanol) prevents memory dysfunction and amyloidogenesis on AD model mice by intraperitoneal LPS (250 μg/kg daily 7 times) injection. In addition, LPS-treated cultured astrocytes and microglial BV-2 cells were investigated for anti-neuroinflammatory and anti-amyloidogenic effect of 4-O-methylhonkiol (0.5, 1 and 2 μM).. Oral administration of 4-O-methylhonokiol ameliorated LPS-induced memory impairment in a dose-dependent manner. In addition, 4-O-methylhonokiol prevented the LPS-induced expression of inflammatory proteins; inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as activation of astrocytes (expression of glial fibrillary acidic protein; GFAP) in the brain. In in vitro study, we also found that 4-O-methylhonokiol suppressed the expression of iNOS and COX-2 as well as the production of reactive oxygen species, nitric oxide, prostaglandin E2, tumor necrosis factor-α, and interleukin-1β in the LPS-stimulated cultured astrocytes. 4-O-methylhonokiol also inhibited transcriptional and DNA binding activity of NF-κB via inhibition of IκB degradation as well as p50 and p65 translocation into nucleus of the brain and cultured astrocytes. Consistent with the inhibitory effect on neuroinflammation, 4-O-methylhonokiol inhibited LPS-induced Aβ1-42 generation, β- and γ-secretase activities, and expression of amyloid precursor protein (APP), BACE1 and C99 as well as activation of astrocytes and neuronal cell death in the brain, in cultured astrocytes and in microglial BV-2 cells.. These results suggest that 4-O-methylhonokiol inhibits LPS-induced amyloidogenesis via anti-inflammatory mechanisms. Thus, 4-O-methylhonokiol can be a useful agent against neuroinflammation-associated development or the progression of AD.

Topics: Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Anti-Inflammatory Agents; Aspartic Acid Endopeptidases; Astrocytes; Avoidance Learning; Biphenyl Compounds; Brain; Cell Line, Transformed; Cyclooxygenase 2; Cytokines; Dinoprostone; Disease Models, Animal; Electrophoretic Mobility Shift Assay; Glial Fibrillary Acidic Protein; In Situ Nick-End Labeling; Inflammation; Lignans; Lipopolysaccharides; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred ICR; Microglia; NF-kappa B; Nitric Oxide; Peptide Fragments

Ginseng extracts show cognition-enhancing effects in Alzheimer's disease (AD) patients. However, little is known about the active components and molecular mechanisms of how ginseng exerts its effects. Recently, we isolated a novel lysophosphatidic acid (LPA) receptor-activating ligand from ginseng, gintonin. AD is caused by amyloid-β protein (Aβ) accumulation. Aβ is derived from amyloid-β protein precursors (AβPPs) through the amyloidogenic pathway. In contrast, non-amyloidogenic pathways produce beneficial, soluble AβPPα (sAβPPα). Here, we describe our investigations of the effect of gintonin on sAβPPα release, Aβ formation, Swedish-AβPP transfection-mediated neurotoxicity in SH-SY5Y neuroblastoma cells, and Aβ-induced neuropathy in mice. Gintonin promoted sAβPPα release in a concentration- and time-dependent manner. Gintonin action was also blocked by the Ca2+ chelator BAPTA, α-secretase inhibitor TAPI-2, and protein-trafficking inhibitor brefeldin. Gintonin decreased Aβ1-42 release and attenuated Aβ1-40-induced cytotoxicity in SH-SY5Y cells. Gintonin also rescued Aβ1-40-induced cognitive dysfunction in mice. Moreover, in a transgenic mouse AD model, long-term oral administration of gintonin attenuated amyloid plaque deposition as well as short- and long-term memory impairment. In the present study, we demonstrated that gintonin mediated the promotion of non-amyloidogenic processing to stimulate sAβPPα release to restore brain function in mice with AD. Gintonin could be a useful agent for AD prevention or therapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Brain; Calcium; Calcium-Binding Proteins; Cell Survival; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Egtazic Acid; Enzyme Inhibitors; Glycoproteins; Humans; Indans; Isoxazoles; Ligands; Maze Learning; Memory Disorders; Metalloproteases; Mice; Mice, Transgenic; Microfilament Proteins; Mutation; Neuroblastoma; Nootropic Agents; Panax; Peptide Fragments; Phytotherapy; Piperidines; Plant Proteins; Presenilin-1; Propionates; Protein Binding; Receptors, Lysophosphatidic Acid; Signal Transduction; Time Factors; Transfection

Endogenously produced hydrogen sulfide (H(2)S) may have multiple functions in brain. An increasing number of studies have demonstrated its anti-inflammatory effects. In the present study, we investigated the effect of sodium hydrosulfide (NaHS, a H(2)S donor) on cognitive impairment and neuroinflammatory changes induced by injections of Amyloid-β(1-40) (Aβ(1-40)), and explored possible mechanisms of action.. We injected Aβ(1-40) into the hippocampus of rats to mimic rat model of Alzheimer's disease (AD). Morris water maze was used to detect the cognitive function. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was performed to detect neuronal apoptosis. Immunohistochemistry analyzed the response of glia. The expression of interleukin (IL)-1β and tumor necrosis factor (TNF)-α was measured by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). The expression of Aβ(1-40), phospho-p38 mitogen-activated protein kinase (MAPK), phospho-p65 Nuclear factor (NF)-κB, and phospho-c-Jun N-terminal Kinase (JNK) was analyzed by western blot.. We demonstrated that pretreatment with NaHS ameliorated learning and memory deficits in an Aβ(1-40) rat model of AD. NaHS treatment suppressed Aβ(1-40)-induced apoptosis in the CA1 subfield of the hippocampus. Moreover, the over-expression in IL-1β and TNF-α as well as the extensive astrogliosis and microgliosis in the hippocampus induced by Aβ(1-40) were significantly reduced following administration of NaHS. Concomitantly, treatment with NaHS alleviated the levels of p38 MAPK and p65 NF-κB phosphorylation but not JNK phosphorylation that occurred in the Aβ(1-40)-injected hippocampus.. These results indicate that NaHS could significantly ameliorate Aβ(1-40)-induced spatial learning and memory impairment, apoptosis, and neuroinflammation at least in part via the inhibition of p38 MAPK and p65 NF-κB activity, suggesting that administration of NaHS could provide a therapeutic approach for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Hippocampus; Hydrogen Sulfide; Inflammation; Male; Memory Disorders; Peptide Fragments; Random Allocation; Rats; Rats, Wistar; Spatial Behavior

β-Amyloid peptides (Aβ) are neurotoxic and contribute to the development of Alzheimer's disease (AD). Ergothioneine (EGT) has been shown to protect against loss of memory and learning abilities in mice. In this study, mice were orally fed EGT (0.5 or 2 mg/kg body weight) for 16 days before treatment (i.c.v) with a single dose of Aβ1-40 in the hippocampus. After resting for 12 days to restore the body weight, the mice were again fed EGT for additional 39 days. Active avoidance tests were conducted on days 37-39 (short-memory avoidance) and on days 37, 44 and 51 (long-memory avoidance). Water maze task was used to evaluate learning and memory abilities by acquisition test and retention test. In both long-memory avoidance and water maze tests, EGT significantly decreased the escape latency and increased the frequency of successful avoidance. Furthermore, EGT significantly prevented Aβ accumulation in the hippocampus and brain lipid peroxidation, restored acetylcholinesterase (AChE) activity, maintained glutathione/glutathione disulfide ratio and superoxide dismutase activity in brain tissues of Aβ1-40-teated mice. Thus, EGT can protect against Aβ-induced loss of memory and learning abilities in mice. Further studies are required to confirm the protective effects of EGT on the development or progression of AD.

Topics: Acetylcholinesterase; Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Animals; Avoidance Learning; Brain; Ergothioneine; Glutathione; Glutathione Disulfide; Hippocampus; Lipid Peroxidation; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Neurons; Neuroprotective Agents; Peptide Fragments; Superoxide Dismutase

The 5-lipoxygenase (5LO) enzyme is upregulated in Alzheimer disease (AD), and its genetic absence reduces Aβ levels in APP mice. However, its functional role in modulating tau neuropathology remains to be elucidated.. To this end, we generated triple transgenic mice (3xTg-AD) overexpressing neuronal 5LO and investigated their phenotype.. Compared with controls, 3xTg-AD mice overexpressing 5LO manifested an exacerbation of memory deficits, plaques, and tangle pathologies. The elevation in Aβ was secondary to an upregulation of γ-secretase pathway, whereas tau hyperphosphorylation resulted from an activation of the Cdk5 kinase. In vitro study confirmed the involvement of this kinase in the 5LO-dependent tau phosphorylation, which was independent of the effect on Aβ.. Our findings highlight the novel functional role that neuronal 5LO plays in exacerbating AD-related tau pathologies. They provide critical preclinical evidence to justify testing selective 5LO inhibitors for AD treatment.

Topics: ADAM Proteins; ADAM10 Protein; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Arachidonate 5-Lipoxygenase; Aspartic Acid Endopeptidases; Brain; Cells, Cultured; Cyclin-Dependent Kinase 5; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Humans; Maze Learning; Membrane Proteins; Memory Disorders; Mice; Mice, Transgenic; NFI Transcription Factors; Peptide Fragments; Phosphorylation; Presenilin-1; Radioimmunoassay; Random Allocation; Signal Transduction; tau Proteins; Transfection

The interaction between gene and environment is known to play a major role in the etiology of several neuropsychiatric disorders, including Alzheimer's disease (AD). The present study evaluated whether environmental manipulations such as social isolation may affect the genetic predisposition to accelerate the onset of AD-related symptoms in an adult APP/PS1 double mutant transgenic mouse model. Transgenic and wild-type male mice were housed either singly or in groups from the age of 3 months, and their behavior was compared at 7 months. Isolation had several effects on the APP/PS1 transgenic mice, including exacerbating the impairment of spatial working memory associated with increased Aβ42/Aβ40 ratio in the hippocampus; increased levels of MnSOD in the CA1-CA3 subregions of the hippocampus, basolateral part of the amygdala (BLA), and locus coeruleus (LC); and decreased numbers of cholinergic cells in the diagonal band of Broca (DB), noradrenergic neurons in LC, serotonergic neurons in the Raphe nucleus, and levels of NMDA 2B receptor (NR2B) in the hippocampus region. Our findings demonstrate the susceptibility of APP/PS1 transgenic adult male mice to environmental manipulation and show that social isolation has remarkable effects on the genetically determined AD-like symptoms.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain Chemistry; Crosses, Genetic; Genetic Predisposition to Disease; Male; Memory Disorders; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Neurotransmitter Agents; Peptide Fragments; Presenilin-1; Protein Processing, Post-Translational; Random Allocation; Receptors, N-Methyl-D-Aspartate; Social Isolation; Superoxide Dismutase

Alzheimer's disease is one of the most devastating neurodegenerative disorders and is characterized by severe memory and cognitive decline. The deposition of beta-amyloid (Aβ) protein is the primary pathology associated with Alzheimer's disease. Current treatments for Alzheimer's disease only offer limited symptomatic alleviation, and more effective therapies are needed for Alzheimer's disease. Our primary data showed that stemazole, a novel small molecule, protected SH-SY5Y cells from toxicity induced by hydrogen peroxide and Aβ aggregates in vitro. In this study, we evaluated the therapeutic effects of a 14-day stemazole treatment in Aβ1-40 aggregate injection rat model of Alzheimer's disease. Administration of stemazole reversed learning and memory deficits induced by the Aβ1-40 aggregates in a dose-dependent manner, as assessed by a Morris water maze task. In addition, the number of Aβ1-40 aggregates was reduced in the hippocampus, as demonstrated by micro-positron emission tomography/computerized tomographic scanning. Finally, stemazole treatment reduced degeneration and the loss of neurons in the hippocampus, as shown by histology and immunohistochemical analysis. The neuroprotective effects of stemazole may be important for its therapeutic efficacy. These results demonstrate that stemazole is effective in the treatment of Aβ1-40 aggregates injection rat model, suggesting that this compound may be used as a therapeutic agent against Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; CA1 Region, Hippocampal; Dentate Gyrus; Disease Models, Animal; Dose-Response Relationship, Drug; Hydrazines; Injections; Memory Disorders; Neurons; Neuroprotective Agents; Oxadiazoles; Peptide Fragments; Protein Multimerization; Protein Structure, Secondary; Rats; Rats, Wistar

An autosomal dominant mutation in the BRI2/ITM2B gene causes familial Danish dementia (FDD). Analysis of FDD(KI) mice, a mouse model of FDD genetically congruous to the human disease since they carry one mutant and one wild-type Bri2/Itm2b allele, has shown that the Danish mutation causes loss of Bri2 protein, synaptic plasticity and memory impairments. BRI2 is a physiological interactor of Aβ-precursor protein (APP), a gene associated with Alzheimer disease, which inhibits processing of APP. Here, we show that APP/Bri2 complexes are reduced in synaptic membranes of FDD(KI) mice. Consequently, APP metabolites derived from processing of APP by β-, α- and γ-secretases are increased in Danish dementia mice. APP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for APP metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that APP and BRI2 functionally interact, and that the neurological effects of the Danish form of BRI2 only occur when sufficient levels of APP are supplied by two alleles. This evidence establishes a pathogenic sameness between familial Danish and Alzheimer's dementias.

Topics: Adaptor Proteins, Signal Transducing; Alzheimer Disease; Amyloid beta-Peptides; Animals; Dementia; Denmark; Disease Models, Animal; Gene Knock-In Techniques; Genetic Carrier Screening; Humans; Male; Membrane Proteins; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutant Chimeric Proteins; Mutation; Peptide Fragments

OBJECTIVE The double transgenic mouse model (APPswe/PS1dE9) of Alzheimer's disease (AD) has been widely used in experimental studies. β-Amyloid (Aβ) peptide is excessively produced in AD mouse brain, which affects synaptic function and the development of central nervous system. However, little has been reported on characterization of this model. The present study aimed to characterize this mouse AD model and its wild-type counterparts by biochemical and functional approaches. METHODS Blood samples were collected from the transgenic and the wild-type mice, and radial arm water maze behavioral test was conducted at the ages of 6 and 12 months. The mice were sacrificed at 12-month age. One hemisphere of the brain was frozen-sectioned for immunohistochemistry and the other hemisphere was dissected into 7 regions. The levels of Aβ1-40, Aβ1-42 and 8-hydroxydeoxyguanosine (8-OHdG) in blood or/and brain samples were analyzed by ELISA. Secretase activities in brain regions were analyzed by in vitro assays. RESULTS The pre-mature death rate of transgenic mice was approximately 35% before 6-month age, and high levels of Aβ(1-40) and Aβ(1-42) were detected in these dead mice brains with a ratio of 1:10. The level of blood-borne Aβ at 6-month age was similar with that at 12-month age. Besides, Aβ(1-40) level in the blood was significantly higher than Aβ(1-42) level at the ages of 6 and 12 months (ratio 2.37:1). In contrast, the level of Aβ(1-42) in the brain (160.6 ng/mg protein) was higher than that of Aβ(1-40) (74 ng/mg protein) (ratio 2.17:1). In addition, the levels of Aβ(1-40) and Aβ(1-42) varied markedly among different brain regions. Aβ(1-42) level was significantly higher than Aβ(1-40) level in cerebellum, frontal and posterior cortex, and hippocampus. Secretase activity assays did not reveal major differences among different brain regions or between wild-type and transgenic mice, suggesting that the transgene PS1 did not lead to higher γ-secretase activity but was more efficient in producing Aβ(1-42) peptides. 8-OHdG, the biomarker of DNA oxidative damage, showed a trend of increase in the blood of transgenic mice, but with no significant difference, as compared with the wild-type mice. Behavioral tests showed that transgenic mice had significant memory deficits at 6-month age compared to wild-type controls, and the deficits were exacerbated at 12-month age with more errors. CONCLUSION These results suggest that this mouse model mimics the early-onset human A

Topics: 8-Hydroxy-2'-Deoxyguanosine; Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Brain; Deoxyguanosine; Disease Models, Animal; Humans; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments

In this study, we investigated whether stress can enhance the toxicity of oligomer Abeta(1-40) in the mouse brain. Stress was applied to the animals, consisting of a 2-day inescapable foot shock followed by 3-weekly situation reminders (SRs). We found that stress significantly affected not only the amygdala-dependent (anxiety) but also the hippocampal-dependent (spatial learning and memory) behaviors through the oxidative damage caused in these two regions. However, oligomer Abeta(1-40) treatment alone did not induce behavioral impairment. In addition, combined oligomer Abeta(1-40) and stress treatment increased the glucocorticoid receptor (GR)/mineralocorticoid receptor (MR) ratio and the expression of corticotrophin releasing factor 1 (CRF-1) receptor in the hippocampus. Changes in the components of the hypothalamic-pituitary-adrenal (HPA) axis, such as the GR/MR ratio and CRF-1 level, were observed, accompanied by increasing Abeta accumulation, oxidative stress, nuclear transcription factor (NF-kappaB) hypoactivity, and apoptotic signaling in the hippocampus, and decreasing calbindin D28K and NMDA receptor 2A/2B (NR2A/2B) in the hippocampus, along with alteration of the cholinergic neurons (ChAT) in the medium septum/diagnoid band (MS/DB), noradrenergic neurons (TH) in the locus coeruleus (LC), and serotonergic neurons (5-HT) in the Raphe nucleus. Therefore, apoptosis and synaptic dysfunction in the hippocampus severely induced the impairment of spatial learning and memory. These results suggest that stress may play an important role in the early stages of Alzheimer's disease (AD), and an antioxidant strategy might be a potential therapeutic approach for stress-mediated disorders.

Topics: Amyloid beta-Peptides; Animals; Disease Models, Animal; Electroshock; Hippocampus; Learning; Learning Disabilities; Locus Coeruleus; Male; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Neurons; Peptide Fragments; Random Allocation; Raphe Nuclei; Space Perception; Stress, Psychological

Alzheimer's disease (AD) is characterized by progressive memory decline and neuropsychiatric symptoms. Despite common emotional symptoms in AD such as anxiety and fear are associated with a more rapid cognitive decline, the pathological mechanisms involved in these behavioral changes remain largely elusive. In this study, we examined the pathological mechanisms of emotional behavior in well-established AD transgenic mice expressing human mutant beta-amyloid (Abeta) precursor protein (APP(Ind) and APP(Sw,Ind)) and tau (3xTg-AD).. We evaluated unconditioned and conditioned fear-induced freezing behavior and spatial memory in APP(Ind), APP(Sw,Ind), and 3xTg-AD transgenic mice. The Abeta and tau pathologies and signaling pathways involved in emotional processing were studied by immunohistochemistry and immunoblotting analyses.. The APP(Ind)/APP(Sw,Ind) and 3xTg-AD transgenic mice displayed at early ages enhanced innate and conditioned fear symptoms and spatial memory deficits coinciding with enhanced accumulation of Abeta in gamma-aminobutyric acid (GABA)ergic and glutamatergic neurons, respectively, of the basolateral amygdala (BLA). Similarly, the number of neurons with intraneuronal Abeta40 and Abeta42 was significantly increased in the BLA of human AD brains. Fear responses might reflect an influence of anxiety, because the anxiolytic compounds valproate, diazepam, and buspirone reduced efficiently unconditioned and conditioned fear responses in APP transgenic mice. In addition, phosphorylation of extracellular signal-regulated kinase (ERK)1/2, which is critical for acquisition and consolidation of fear conditioning, was increased in the amygdala of APP transgenic mice after cued conditioning.. We propose a deleterious role of intraneuronal Abeta on amygdala-dependent emotional responses by affecting the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amygdala; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anxiety; Conditioning, Classical; Disease Models, Animal; DNA-Binding Proteins; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Fear; Female; Gene Expression Regulation; Humans; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Peptide Fragments; Polycomb-Group Proteins; Presenilin-1; Signal Transduction; Statistics, Nonparametric; tau Proteins; Transcription Factors; Valproic Acid

The present study was undertaken to investigate the protective effects of icariin on the learning and memory abilities in Alzheimer's disease model rats and explore its protection mechanisms. Beta-amyloid peptide (Abeta) is a key etiology in Alzheimer's disease and targeting on Abeta production and assembly is a new therapeutic strategy. Six-month (400-600 g) Wistar rats were unilaterally injected with amyloid beta-protein fragment 25-35 (Abeta(25-35)) 10 microg (5 g/l, 2 microl) into the right hippocampus. The day following Abeta injection, icariin 30, 60 or 120 mg/kg was administered by gavage for 14 days. The ability of spatial learning and memory of the animals was tested by the Morris water maze. In place navigation test, icariin significantly decreased the mean escape latency and searching distance. In the space probing test, icariin increased remarkably the searching time and searching distance in the quadrant where the platform was originally located. All tests indicated icariin improved the ability of spatial learning and memory in Alzheimer's disease model rats. Furthermore, immunohistochemistry and real time RT-PCR analysis showed that icariin significantly reduced the contents of Abeta(1-40) and the mRNA levels of beta-secretase in the hippocampus and increased the mRNA level of superoxide dismutase-2, but it had no apparent effects on the immunostain and mRNA level of amyloid protein precursor. These results demonstrate that icariin can improve the learning and memory abilities in Abeta(25-35)-induced Alzheimer's disease rats. The mechanisms appear to be due to the decreased production of insoluble fragments of Abeta through suppression of beta-secretase expression.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Flavonoids; Gene Expression Regulation, Enzymologic; Hippocampus; Learning; Male; Memory Disorders; Peptide Fragments; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Solubility

Chronic infusion of human amyloid-beta 1-40 (Abeta) in the lateral ventricle (LV) of rats is associated with memory impairment and increase of kinin receptors in cortical and hippocampal areas. Deletion of kinin B1 or B2 receptors abolished memory impairment caused by an acute single injection of Abeta in the LV. As brain tissue and kinin receptors could unlikely react to acute or chronic administration of a similar quantity of Abeta, we evaluated the participation of B1 or B2 receptors in memory impairment after chronic infusion of Abeta. Male C57Bl/6J (wt), knock-out B1 (koB1) or B2 (koB2) mice (12weeks of age) previously trained in a two-way shuttle-box and achieving conditioned avoidance responses (CAR, % of 50 trials) were infused with AB (550pmol, 0.12microL/h, 28days) or vehicle in the LV using a mini-osmotic pump. They were tested before the surgery (T0), 7 and 35days after the infusion started (T7; T35). In T0, no difference was observed between CAR of the control (Cwt=59.7+/-6.7%; CkoB1=46.7+/-4.0%; CkoB2=64.4+/-5.8%) and Abeta (Abetawt=66.0+/-3.0%; AbetakoB1=66.8+/-8.2%; AbetakoB2=58.7+/-5.9%) groups. In T7, AbetakoB2 showed a significant decrease in CAR (41.0+/-8.6%) compared to the control-koB2 (72.8+/-2.2%, P<0.05). In T35, a significant decrease (P<0.05) was observed in Abetawt (40.7+/-3.3%) and AbetakoB2 (41.2+/-10.7%) but not in the AbetakoB1 (64.0+/-14.0%) compared to their control groups. No changes were observed in the controls at T35. We suggest that in chronic infusion of BA, B1 receptors could play an important role in the neurodegenerative process. Conversely, the premature memory impairment of koB2 suggests that it may be a protective factor.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Avoidance Learning; Brain; Male; Memory; Memory Disorders; Mice; Mice, Knockout; Motor Activity; Neurons; Peptide Fragments; Receptor, Bradykinin B1; Receptor, Bradykinin B2

Amyloid precursor protein (APP) is strongly related to the onset of Alzheimer's disease. It possesses cleavage sites for beta- and gamma-secretases, and the resulting cleaved products (amyloid-beta peptides) are capable of causing neurotoxicity. Such cleavage is promoted by the Swedish and London mutations (APPSwe/Lon) inside the APP gene. Here, we characterized APPSL transgenic mice (APPSL-Tg) to determine the effects of this mutation. We observed that both the amount of insoluble amyloid-beta and the ratio of amyloid-beta 42/40 increased promptly in the brain during 6-16 months of age. Amyloid-beta plaques were observed in whole brain sections at 12 months. In contrast, the spatial memory assessed by the Morris water maze task was already impaired at 3 months, which suggested that the APPSL-Tg mice may represent an early-onset model of familial Alzheimer's disease. Furthermore, the levels of LAMP-1, a marker protein of lysosome, increased in the brain at 28 months. Such LAMP-1 protein was detected around the amyloid-beta plaques at the hippocampal regions of the APPSL-Tg mice. Our results suggested that the increase in LAMP-1 was enhanced by the accumulation of amyloid-beta occurring during aging. Our findings coincided with the pathological hallmarks of Alzheimer's disease.

Topics: Age of Onset; Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Disease Models, Animal; Hippocampus; Lysosomal Membrane Proteins; Maze Learning; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Plaque, Amyloid; Protease Nexins; Receptors, Cell Surface

Amyloid beta (Abeta) peptide is closely related to the onset of Alzheimer's disease (AD). A high-cholesterol or high-energy diet was demonstrated to stimulate Abeta formation and deposition in the amyloid precursor protein (APP) pathway and, oppositely, downregulate the secretion of the neuroprotective soluble APP alpha-fragment (sAPPalpha). Monascus-fermented red mold rice (RMR) including multiple cholesterol-lowering agents, antioxidants, and anti-inflammatory agents has been proven to ameliorate Abeta40 infusion-induced memory deficit in our previous study. In this study, the ethanol extract of RMR (RE) and natural RMR were respectively tested for their effect on the mediation of the proteolytic process of APP in cholesterol-treated human neuroblastoma IMR32 cell, as well as their effect on memory and learning ability and the expression of AD risk factors in intracerebroventricular Abeta40-infused hyperlipidemic rats. In the results, RE suppressed cholesterol-raised beta-secretase activity and further resulted in the increase of sAPPalpha secretion in the IMR32 cell. In the animal test, RMR potently reversed the memory deficit in the water maze and passive avoidance tasks. RMR administration could prevent against Abeta40 infusion plus the great damage caused by a high energy diet in hippocampus and cortex involved in the raise of thiobarbituric acid reactive substances and reactive oxygen species. The neuroprotection provided by RMR downregulates Abeta40 formation and deposition by suppressing the cholesterol-raised beta-secretase activity and apolipoprotein E expression, as well as mediates the proteolytic process of APP toward neuroprotective sAPPalpha secretion in hippocampus.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Brain; Cerebral Ventricles; Cholesterol; Fungi; Humans; Hyperlipidemias; Infusions, Intravenous; Learning Disabilities; Lovastatin; Male; Maze Learning; Memory Disorders; Monascus; Oryza; Peptide Fragments; Rats; Rats, Wistar; Reactive Oxygen Species; Thiobarbituric Acid Reactive Substances

beta-Site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates amyloid-beta (Abeta) generation that is central to the pathophysiology of Alzheimer's disease (AD). Therefore, lowering Abeta levels by BACE1 manipulations represents a key therapeutic strategy, but it remains unclear whether partial inhibition of BACE1, as expected for AD treatments, can improve memory deficits. In this study, we used heterozygous BACE1 gene knockout (BACE1+/-) mice to evaluate the effects of partial BACE1 suppression on different types of synaptic and cognitive dysfunctions in Alzheimer's transgenic mice (5XFAD model). We found that approximately 50% BACE1 reductions rescued deficits of 5XFAD mice not only in hippocampus-dependent memories as tested by contextual fear conditioning and spontaneous alternation Y-maze paradigms but also in cortex-dependent remote memory stabilization during 30 days after contextual conditioning. Furthermore, 5XFAD-associated impairments in long-term potentiation (a synaptic model of learning and memory) and declines in synaptic plasticity/learning-related brain-derived neurotrophic factor-tyrosine kinase B signaling pathways were prevented in BACE1+/-.5XFAD mice. Finally, these improvements were related with reduced levels of beta-secretase-cleaved C-terminal fragment (C99), Abeta peptides and plaque burden in relevant brain regions of BACE1+/-.5XFAD mice. Therefore, our findings provide compelling evidence for beneficial effects of partially BACE1-inhibiting approaches on multiple forms of functional defects associated with AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Aspartic Acid Endopeptidases; Conditioning, Classical; Disease Models, Animal; Electric Stimulation; Enzyme-Linked Immunosorbent Assay; Excitatory Postsynaptic Potentials; Fear; Gene Expression Regulation; Humans; In Vitro Techniques; Long-Term Potentiation; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Mutation; Neuronal Plasticity; Patch-Clamp Techniques; Peptide Fragments; Presenilin-1

Alzheimer's disease (AD) is progressive dementia with senile plaques composed of beta-amyloid (Abeta). Recent studies suggest that synaptic dysfunction is one of the earliest events in the pathogenesis of AD. Here we provide the first experimental evidence that a change in the level of dynamin 1 induced by Abeta correlates with memory impairment in vivo. We treated rats with transient cerebral ischemia with oligomeric forms of Abeta (Abeta oligomers), including dimers, trimers, and tetramers, intracerebroventricularly. The combination of Abeta oligomers and cerebral ischemia, but not cerebral ischemia alone, significantly impaired memory and decreased the level of dynamin 1, which plays a critical role in synaptic vesicle recycling, but did not affect the levels of other synaptic proteins, such as synaptophysin and synaptobrevin, in the hippocampus. Furthermore, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine prevented memory impairment and dynamin 1 degradation, suggesting that these changes might be mediated by NMDA receptors. These results suggest that Abeta oligomers induce memory impairment via dynamin 1 degradation, which may imply that dynamin 1 degradation is one of the causes of synaptic dysfunction in AD.

Topics: Amyloid beta-Peptides; Animals; Dynamin I; Excitatory Amino Acid Antagonists; Hippocampus; Ischemic Attack, Transient; Male; Maze Learning; Memantine; Memory Disorders; PC12 Cells; Peptide Fragments; Protein Multimerization; R-SNARE Proteins; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Synaptophysin

Clinical studies suggest that agonists at peroxisome proliferator-activated receptor gamma (PPARgamma) may exert beneficial effects in patients with mild-to-moderate Alzheimer's disease (AD), but the mechanism for the potential therapeutic interest of this class of drugs has not yet been elucidated. Here, in mice overexpressing mutant human amyloid precursor protein, we found that chronic treatment with rosiglitazone, a high-affinity agonist at PPARgamma, facilitated beta-amyloid peptide (Abeta) clearance. Rosiglitazone not only reduced Abeta burden in the brain but, importantly, almost completely removed the abundant amyloid plaques observed in the hippocampus and entorhinal cortex of 13-month-old transgenic mice. In the hippocampus, neuropil threads containing phosphorylated tau, probably corresponding to dystrophic neurites, were also decreased by the drug. Rosiglitazone switched on the activated microglial phenotype, promoting its phagocytic ability, reducing the expression of proinflammatory markers and inducing factors for alternative differentiation. The decreased amyloid pathology may account for the reduction of p-tau-containing neuropil threads and for the rescue of impaired recognition and spatial memory in the transgenic mice. This study provides further insights into the mechanisms for the beneficial effect of rosiglitazone in AD patients.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; CD11b Antigen; CD36 Antigens; Cyclooxygenase 2; Cytokines; Gene Expression Regulation; Humans; Hypoglycemic Agents; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neuropsychological Tests; Peptide Fragments; Recognition, Psychology; Rosiglitazone; tau Proteins; Thiazolidinediones

The development of novel therapeutic strategies for Alzheimer's disease (AD) represents one of the biggest unmet medical needs today. Application of neurotrophic factors able to modulate neuronal survival and synaptic connectivity is a promising therapeutic approach for AD. We aimed to determine whether the loco-regional delivery of ciliary neurotrophic factor (CNTF) could prevent amyloid-beta (Abeta) oligomer-induced synaptic damages and associated cognitive impairments that typify AD. To ensure long-term administration of CNTF in the brain, we used recombinant cells secreting CNTF encapsulated in alginate polymers. The implantation of these bioreactors in the brain of Abeta oligomer-infused mice led to a continuous secretion of recombinant CNTF and was associated with the robust improvement of cognitive performances. Most importantly, CNTF led to full recovery of cognitive functions associated with the stabilization of synaptic protein levels in the Tg2576 AD mouse model. In vitro as well as in vivo, CNTF activated a Janus kinase/signal transducer and activator of transcription-mediated survival pathway that prevented synaptic and neuronal degeneration. These preclinical studies suggest that CNTF and/or CNTF receptor-associated pathways may have AD-modifying activity through protection against progressive Abeta-related memory deficits. Our data also encourage additional exploration of ex vivo gene transfer for the prevention and/or treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apoptosis; Brain; Cell Count; Cell- and Tissue-Based Therapy; Cells, Cultured; Ciliary Neurotrophic Factor; Disease Models, Animal; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Green Fluorescent Proteins; Humans; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neurons; Peptide Fragments; Signal Transduction; Synapses; Synaptosomes; Time Factors; Transfection

Cyclic AMP signaling plays an important role in memory loss associated with Alzheimer's disease (AD). However, little is known about whether inhibition of phosphodiesterase-4 (PDE4), which increases intracellular cAMP, reverses β-amyloid peptide (Aβ)-induced memory deficits.. Experiments were performed to demonstrate the effect of the PDE4 inhibitor rolipram on memory impairment produced by Aβ1-40 (Aβ40) or its core fragment Aβ25-35.. We tested memory using Morris water-maze and passive avoidance tasks and examined expression of phosphorylated cAMP response-element binding protein (pCREB) in the hippocampus in rats treated with Aβ25-35 or Aβ40 into bilateral CA1 subregions, with or without rolipram administration.. Aβ25-35 (10 μg/side) increased escape latency during acquisition training and decreased swimming time and distance in the target quadrant in the water-maze probe trial; it also decreased 24-h retention in the passive avoidance paradigm. All these were reversed by chronic administration of rolipram (0.5 mg/kg). Similarly, Aβ40 (4 μg/side) produced memory impairment, as demonstrated by decreased retention in passive avoidance; this was also reversed by repeated treatment with rolipram. In addition, rolipram blocked extinction of memory during the 32-day testing period in the passive avoidance test. Further, Aβ40 decreased pCREB expression in the hippocampus, which was also reversed by rolipram; the changes in pCREB were highly correlated with those in memory.. These results suggest that the PDE4 inhibitor rolipram reverses cognitive deficits associated with AD most likely via increased cAMP/CREB signaling in the hippocampus; PDE4 could be a target for drugs that improve cognition in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Avoidance Learning; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Hippocampus; Male; Maze Learning; Memory Disorders; Peptide Fragments; Phosphodiesterase 4 Inhibitors; Rats; Rats, Sprague-Dawley; Rolipram; Swimming

The accumulation of amyloid-beta (Aβ) peptides in the brain of human and rodents has been associated with the activation of glial cells, neuroinflammatory and oxidative responses, and cognitive deficits. These oxidative changes leave glutamate transporters more vulnerable and may result in reduction of their functions, resulting in excitotoxic damage. Herein, we evaluated the effects of atorvastatin, a HMG-CoA reductase inhibitor, in molecular and behavioral alterations induced by a single intracerebroventricular injection of aggregated Aβ(1-40) (400 pmol) in mice. An increased glial fibrillar acidic protein (GFAP) expression and cyclooxygenase-2 (COX-2) levels, as well as increased lipid peroxidation and impairment in the glutathione antioxidant system and cell degeneration was found in the hippocampus of Aβ(1-40)-treated mice. Aβ(1-40) also induced a marked decrease in glutamatergic transporters (GLAST and GLT-1) expression and in l-[³H] glutamate uptake in mice hippocampus, in addition to spatial learning and memory deficits. Atorvastatin (10 mg/kg/day v.o.) was administered after Aβ(1-40) injection and through seven consecutive days. Atorvastatin treatment was neuroprotective against cell degeneration induced by Aβ(1-40), reducing inflammatory and oxidative responses and increasing the expression of glutamatergic transporters. On the other hand, atorvastatin did not reverse the cognitive impairments and failed to alter the hippocampal glutamate uptake in Aβ(1-40)-treated mice. These results reinforce and extend the notion of the potential neuroprotective action of atorvastatin against the neuronal toxicity induced by Aβ(1-40). In addition, the present findings suggest that the spatial learning and memory deficits induced by Aβ peptides in rodents may not be entirely related to neuronal damage.

Topics: Amino Acid Transport System X-AG; Amyloid beta-Peptides; Analysis of Variance; Animals; Animals, Newborn; Astrocytes; Atorvastatin; Cell Death; Cyclooxygenase 2; Encephalitis; Fluoresceins; Gene Expression Regulation; Glutamic Acid; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Heptanoic Acids; Hippocampus; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Learning Disabilities; Male; Maze Learning; Memory Disorders; Mice; Nerve Tissue Proteins; Neurons; Organic Chemicals; Oxidative Stress; Peptide Fragments; Propidium; Pyrroles; Tritium

Accumulating evidence has pointed that a variety of lipids could exert their beneficial actions against dementia including Alzheimer disease and age-related cognitive decline via diverse signaling pathways. Endoplasmic reticulum (ER) stress-induced neuronal apoptosis, on the other hand, is a critical factor for pathogenesis of neurodegenerative diseases such as Alzheimer disease and Parkinson disease, senile dementia, and ischemic neuronal damage. The present study examined the effects of 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine (DLPhtEtn), a phospholipid, on ER stress-induced neuronal death and age-related cognitive disorders.. PC-12 cell viability was assayed before and after treatment with amyloid-β(1-40) peptide or thapsigargin in the presence and absence of DLPhtEtn. A series of behavioral tests were performed for senescence-accelerated mouse-prone 8 (SAMP8) mice after 7-month oral administration with polyethylene glycol (PEG) or DLPhtEtn and then, the number of hippocampal neurons was counted.. Amyloid-β(1-40) peptide or thapsigargin is capable of causing ER stress-induced apoptosis. DLPhtEtn (30 μM) significantly inhibited PC-12 cell death induced by amyloid-β(1-40) peptide or thapsigargin. In the water maze test, oral administration with DLPhtEtn (1 mg/kg) for 7 months (three times a week) significantly shortened the prolonged retention latency for SAMP8 mice. In contrast, DLPhtEtn had no effect on the acquisition and retention latencies in both the open field test and the passive avoidance test for SAMP8 mice. Oral administration with DLPhtEtn (1 mg/kg) for 7 months prevented a decrease in the number of hippocampal neurons for SAMP8 mice.. The results of the present study show that DLPhtEtn ameliorates age-related spatial memory decline without affecting motor activities or fear memory, possibly by protecting hippocampal neuronal death. DLPhtEtn, thus, might exert its beneficial action against senile dementia and neurodegenerative diseases such as Alzheimer disease.

Topics: Age Factors; Amyloid beta-Peptides; Animals; Cell Death; Cell Survival; Disease Models, Animal; Drug Administration Schedule; Hippocampus; Male; Memory Disorders; Mice; Mice, Inbred Strains; Neurons; PC12 Cells; Peptide Fragments; Phosphatidylethanolamines; Rats; Thapsigargin

Amyloidβ-protein (Aβ) assembly into toxic fibrillar structures is seminal in development of senile plaques, the pathological hallmark of Alzheimer's disease. Blocking this process could have a therapeutic value. β-sheet breaker peptides (βSBP) decrease Aβ fibrillogenesis and neurotoxicity by preventing or dissolving misfolded Aβ aggregates. The present study investigated the effects of βSBPs on Aβ40-related neuropathology, memory impairment in 8-armed radial maze and expression of Aβ40 in brain and serum. Aβ40 was injected into amygdaloid nucleus followed 8 days later by octapeptideβSBPs 15-22, 16-23 and 17-24. Aβ40 was detected not only in amygdala, but also in serum. Aβ40 induced cellular changes in amygdala and additionally in hippocampus. Aβ40 decreased correct choices, whereas increased errors (both number of arms revisited and total number of revisits) and latency of completing the maze test. The βSBPs decreased Aβ40-induced pathological changes, memory impairment and Aβ40 expression in serum. The βSBP15-22 distinctively decreased the total errors on day 14. The present results show that octapeptide βSBPs corrected Aβ40-induced memory impairment, and support investigation of βSBPs as a promising treatment of diseases characterized by neurodegeneration and memory impairment such as Alzheimer's disease.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Male; Memory Disorders; Peptide Fragments; Rats; Rats, Sprague-Dawley

Elevation of intracranial soluble amyloid-beta (Abeta) levels has been implicated in the pathogenesis of Alzheimer's disease (AD). Intracellular events in neurons, which lead to memory loss in AD, however, remain elusive. Humanin (HN) is a short neuroprotective peptide abolishing Abeta neurotoxicity. Recently, we found that HN derivatives activate the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis. We here report that an HN derivative named colivelin completely restored cognitive function in an AD model (Tg2576) by activating the JAK2/STAT3 axis. In accordance, immunofluorescence staining using a specific antibody against phospho- (p-) STAT3 revealed that p-STAT3 levels in hippocampal neurons age-dependently decreased in both AD model mice and AD patients. Intracerebroventricular administration of Abeta1-42 downregulated p-STAT3 whereas passive immunization with anti-Abeta antibody conversely restored hippocampal p-STAT3 levels in Tg2576 mice, paralleling the decrease in the brain Abeta burden. Abeta1-42 consistently modulated p-STAT3 levels in primary neurons. Pharmacological inhibition of the JAK2/STAT3 axis not only induced significant loss of spatial working memory by downregulating an acetylcholine-producing enzyme choline acetyltransferase but also desensitized the M(1)-type muscarinic acetylcholine receptor. Thus, we propose a novel theory accounting for memory impairment related to AD: Abeta-dependent inactivation of the JAK2/STAT3 axis causes memory loss through cholinergic dysfunction. Our findings provide not only a novel pathological hallmark in AD but also a novel target in AD therapy.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Enzyme Inhibitors; Exploratory Behavior; Gene Expression Regulation; Hippocampus; Humans; Intracellular Signaling Peptides and Proteins; Janus Kinase 2; Maze Learning; Memory Disorders; Mice; Mice, Inbred ICR; Mice, Transgenic; Mutation; Nerve Tissue Proteins; Neurons; Peptide Fragments; Presenilin-1; Receptor, Muscarinic M1; STAT3 Transcription Factor

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

Acetylcholine (ACh) release is one of the key factors in memory mechanisms. To clarify whether beta-amyloid (Abeta) induces a disturbance of the cholinergic system leading to memory impairment, we examined memory impairment and measured hippocampal ACh release in Tg2576 (Tg) mice that over-express the Swedish mutant amyloid precursor protein (APPsw). Furthermore, we examined Abeta burden with aging. Tg mice aged 9-11 months, but not aged 4-6 months, showed memory impairment in the 8-arm radial maze behavior test. Spontaneous ACh release was not altered in Tg mice compared with age-matched control mice at 4-6 or 9-11 months of age. On the other hand, high-K(+)-evoked ACh release was decreased in Tg mice aged 9-11 months, but not in Tg mice aged 4-6 months. Hippocampal Abeta increased in an age-dependent manner, but evident amyloid plaques were not found in the hippocampus of Tg mice aged 11 months. These results suggest that memory impairment in Tg mice could be attributed to cholinergic synapse dysfunction that could not be caused predominantly by amyloid plaques. Measuring ACh release in this model might be a useful index for the screening of new drugs to treat the early-phase of Alzheimer's disease.

Topics: Acetylcholine; Aging; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Disease Models, Animal; Hippocampus; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Peptide Fragments; Plaque, Amyloid; Potassium

A strong link is indicated between cardiovascular disease (CVD) and risk for developing Alzheimer's disease (AD), which may be exacerbated by the major AD genetic risk factor apolipoprotein Eepsilon4 (APOEepsilon4). Since subjective memory complaint (SMC) may potentially be an early indicator for cognitive decline, we examined CVD risk factors in a cohort of SMC. As amyloid-beta (Abeta) is considered to play a central role in AD, we hypothesized that the CVD risk profile (increased LDL, reduced HDL, and increased body fat) would be associated with plasma Abeta levels. We explored this in 198 individuals with and without SMC (average age = 63 years). Correlations between Abeta40 and HDL were observed, which were stronger in non-APOEepsilon4 carriers (rho = -0.315, p < 0.001) and in SMC (rho = -0.322, p = 0.01). There was no relationship between percentage body fat and Abeta40 in this cohort. Age and HDL remained predictive for plasma Abeta40 using multivariate regression analysis. We report a novel negative association between HDL and Abeta, which if demonstrated to be causal has implications for the development of lifestyle interventions and/or novel therapeutics. The relationship between HDL and Abeta and the potential significance of such an association needs to be validated in a larger longitudinal study.

Topics: Absorptiometry, Photon; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Cardiovascular System; Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Peptide Fragments; Risk Factors; Statistics, Nonparametric

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

We examined the effects of voluntary (16 weeks of wheel running) and forced (16 weeks of treadmill running) exercise on memory-related behavior, hippocampal volume, thioflavine-stained plaque number, and soluble Abeta levels in brain tissue in the Tg2576 mouse model of Alzheimer's disease (AD). Voluntary running animals spent more time investigating a novel object in a recognition memory paradigm than all other groups. Also, voluntary running animals showed fewer thioflavine S stained plaques than all other groups, whereas forced running animals showed an intermediate number of plaques between voluntary running and sedentary animals. Both voluntary and forced running animals had larger hippocampal volumes than sedentary animals. However, levels of soluble Abeta-40 or Abeta-42 did not significantly differ among groups. The results indicate that voluntary exercise may be superior to forced exercise for reducing certain aspects of AD-like deficits - i.e., plaque deposition and memory impairment, in a mouse model of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Benzothiazoles; Cerebral Cortex; Disease Models, Animal; Hippocampus; Humans; Memory; Memory Disorders; Mice; Mice, Transgenic; Organ Size; Peptide Fragments; Physical Conditioning, Animal; Protease Nexins; Random Allocation; Receptors, Cell Surface; Recognition, Psychology; Thiazoles; Time Factors

Mitochondrial dysfunction and oxidative stress are involved in Alzheimer disease (AD) pathogenesis. In human AD brains, the activity of the alpha-ketoglutarate dehydrogenase enzyme complex (alpha-KGDHC) is reduced. KGDHC is mostly involved in NADH production. It can also participate in oxidative stress and reactive oxygen species (ROS) production. The mitochondrial dihydrolipoyl succinyltransferase enzyme (DLST) is a key subunit specific to the alpha-KGDHC. In cultured cells, reduction of DLST increased H(2)O(2)-induced ROS generation and cell death. Thus, we asked whether partial genetic deletion of DLST could accelerate the onset of AD pathogenesis, using a transgenic mouse model of amyloid deposition crossed with DLST(+/-) mice. Tg19959 mice, which carry the human amyloid precursor protein with two mutations, develop amyloid deposits and progressive behavioral abnormalities. We compared Tg19959 mice to Tg19959-DLST(+/-) littermates at 2-3 months of age and studied the effects of DLST deficiency on amyloid deposition, spatial learning and memory, and oxidative stress. We found that alpha-KGDHC activity was reduced in DLST(+/-) mice. We also found that DLST deficiency increased amyloid plaque burden, Abeta oligomers, and nitrotyrosine levels and accelerated the occurrence of spatial learning and memory deficits in female Tg19959 mice. Our data suggest that alpha-KGDHC may be involved in AD pathogenesis through increased mitochondrial oxidative stress.

Topics: Acyltransferases; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Animals; Disease Models, Animal; Female; Male; Memory Disorders; Mice; Mice, Transgenic; Mitochondria; Oxidative Stress; Peptide Fragments

Mutations in the Presenilin 2 gene (PSEN2) are rare causes of Alzheimer's disease (AD). Pathogenic mutations in the genes associated with autosomal dominant inherited AD have been shown to alter processing of the amyloid precursor protein (APP) resulting in a relative increase of the amount of Abeta42 peptide.. We present a patient with neuropathologically confirmed early-onset AD characterized by profound language impairment. The patient was heterozygous for a novel missense mutation in exon 11 of the PSEN2 gene leading to a predicted amino acid substitution from valine to methionine in position 393, a conserved residue. However, in vitro expression of PSEN2 V393M cDNA did not result in detectable increase of the secreted Abeta42/40 peptide ratio. The mutation was not found in 384 control individuals tested.. The possible pathogenic nature of the mutation is not clarified. We discuss the limitations of functional PSEN2 studies and the challenges associated with genetic counselling of family members at risk.

Topics: Age of Onset; Alzheimer Disease; Amino Acid Substitution; Amyloid beta-Peptides; Brain; Cell Line; DNA, Complementary; Exons; Heterozygote; Humans; Language Disorders; Male; Memory Disorders; Middle Aged; Mutation, Missense; Neuropsychological Tests; Pedigree; Peptide Fragments; Point Mutation; Presenilin-2; Recombinant Fusion Proteins; Transfection

Recent findings suggest that hypercholesterolemia may contribute to the onset of Alzheimer's disease-like dementia but the underlying mechanisms remain unknown. In this study, we evaluated the cognitive performance in rodent models of hypercholesterolemia in relation to neuroinflammatory changes and amyloid precursor protein (APP) processing, the two key parameters of Alzheimer's disease pathogenesis. Groups of normal C57BL/6 and low density lipoprotein receptor (LDLR)-deficient mice were fed a high fat/cholesterol diet for an 8-week period and tested for memory in a radial arm maze. It was found that the C57BL/6 mice receiving a high fat diet were deficient in handling an increasing working memory load compared with counterparts receiving a control diet while the hypercholesterolemic LDLR-/- mice showed impaired working memory regardless of diet. Immunohistochemical analysis revealed the presence of activated microglia and astrocytes in the hippocampi from high fat-fed C57BL/6 mice and LDLR-/- mice. Consistent with a neuroinflammatory response, the hyperlipidemic mice showed increased expression of cytokines/mediators including tumor necrosis factor-alpha, interleukin-1beta and -6, nitric oxide synthase 2, and cycloxygenase 2. There was also an induced expression of the key APP processing enzyme i.e. beta-site APP cleaving enzyme 1 in both high fat/cholesterol-fed C57BL/6 and LDLR-/- mice accompanied by an increased generation of C-terminal fragments of APP. Although ELISA for beta-amyloid failed to record significant changes in the non-transgenic mice, a threefold increase in beta-amyloid 40 accumulation was apparent in a strain of transgenic mice expressing wild-type human APP on high fat/cholesterol diet. The findings link hypercholesterolemia with cognitive dysfunction potentially mediated by increased neuroinflammation and APP processing in a non-transgenic mouse model.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Brain; Cholesterol; Cytokines; Dietary Fats; Disease Models, Animal; Encephalitis; Hypercholesterolemia; Maze Learning; Memory Disorders; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Peptide Fragments; Receptors, LDL; Up-Regulation

Amyloid beta (Abeta) peptide related to the onset of Alzheimer's disease (AD) damaged neurons and further resulted in dementia. Monascus-fermented red mold rice (RMR), a traditional Chinese medicine as well as health food, includes monacolins (with the same function as statins) and multifunctional metabolites. In this study, ethanol extract of RMR (RE) was used to evaluate neuroprotection against Abeta40 neurotoxicity in PC12 cells. Furthermore, the effects of dietary administration of RMR on memory and learning abilities are confirmed in an animal model of AD rats infused with Abeta40 into the cerebral ventricle. During continuous Abeta40 infusion for 28 days, the rats of test groups were administered RMR or lovastatin. Memory and learning abilities were evaluated in the water maze and passive avoidance tasks. After sacrifice, cerebral cortex and hippocampus were collected for the examination of AD risk factors. The in vitro results clearly indicate that RE provides stronger neuroprotection in rescuing cell viability as well as repressing inflammatory response and oxidative stress. RMR administration potently reverses the memory deficit in the memory task. Abeta40 infusion increases acetylcholinesterase activity, reactive oxygen species, and lipid peroxidation and decreases total antioxidant status and superoxide dismutase activity in brain, but these damages were potently reversed by RMR administration, and the protection was more significant than that with lovastatin administration. The protection provided by RMR is able to prevent Abeta fibrils from being formed and deposited in hippocampus and further decrease Abeta40 accumulation, even though Abeta40 solution was infused into brain continuously.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Brain; Disease Models, Animal; Drug Interactions; Injections, Intraventricular; Learning; Lovastatin; Male; Maze Learning; Memory Disorders; Nerve Tissue Proteins; Oryza; PC12 Cells; Peptide Fragments; Phytotherapy; Plant Extracts; Rats; Rats, Wistar

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

We investigated the effects of memantine and donepezil on amyloid beta (Abeta)-induced memory impairment in rats, which was assessed by a delayed-matching to position (DMPT) paradigm in three-lever operant chambers. Aggregated Abeta1-40 was microinjected bilaterally (1 nmol/side) into both CA1 and CA3 subfields of the hippocampus in rats that had previously performed the DMTP task. Memantine (20 mg/(kg day), s.c.) was continuously infused by an osmotic minipump for 4 weeks from 3 days before the microinjection of Abeta. Donepezil (2.5 mg/kg, p.o.) was administered 60 min before the DMTP test session. Bilateral microinjections of Abeta1-40 into the hippocampus resulted in a delayed, but persistent impairment of DMTP performance, which appeared more than 50 days after the injection. Memantine prevented the development of Abeta-induced memory impairment, while donepezil symptomatically alleviated the deficits. Because of a ceiling effect, the combination of donepezil with memantine failed to produce any additive or synergic effects. These results support the clinical data showing that memantine and donepezil are effective for the treatment of Alzheimer's disease. Moreover, it is suggested that memantine is effective for preventing Abeta-induced short-term memory impairment.

Topics: Amyloid beta-Peptides; Animals; Cholinesterase Inhibitors; Conditioning, Operant; Donepezil; Drug Administration Routes; Drug Interactions; Excitatory Amino Acid Antagonists; Food Deprivation; Hippocampus; Indans; Male; Memantine; Memory Disorders; Peptide Fragments; Piperidines; Rats; Rats, Inbred F344; Reaction Time; Time Factors

The purpose of this paper is to study the basic pharmacological action of sarsasapogenin, a sapogenin from the Chinese medicinal herb Rhizoma Anemarrhenae, (abbreviated as ZMS in this paper), on learning ability and memory of three animal models: aged rats and two neurodegeneration models produced either by single unilateral injection of beta-amyloid 1-40 (Abeta1-40) plus ibotenic acid (Ibot A) or by bilateral injection of Ibot A alone into nucleus basalis magnocellularis. Y-maze test and step-through test revealed that learning ability and memory were impaired in the three models and were improved by oral administration of ZMS. ZMS did not inhibit acetylcholinesterase nor did it occupy the binding sites of muscarinic acetylcholine receptor (M receptor), hence it is neither an cholinesterase inhibitor nor an agonist or antagonist of M receptors. On the other hand, the densities of total M receptor and its M1 subtype in the brain of the three models were significantly lower than control rats, and ZMS significantly raised the densities of total M receptors and its M1 subtype. Linear regression revealed significant correlation between the learning ability/memory and the density of either total M receptor or its M1 subtype. Autoradiographic study with 3H-pirenzipine showed that the M1 subtype density was significantly lowered in cortex, hippocampus and striatum of aged rats, and ZMS could reverse these changes towards normal control level. Interestingly, the M1 receptor density after ZMS administration only approached but did not exceed that of normal young control rats. Therefore, ZMS seems to represent a new approach to the pharmacological regulation of learning and memory and appears to be not simply palliative but may modify the progression of the disease.

Topics: Acetylcholinesterase; Age Factors; Amyloid beta-Peptides; Animals; Autoradiography; Brain; Disease Models, Animal; Excitatory Amino Acid Agonists; Female; Ibotenic Acid; Immunohistochemistry; Male; Maze Learning; Memory Disorders; Nerve Degeneration; Neurotoxins; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Spirostans

FE65 is a multimodular adapter protein that is expressed predominantly in brain. Its C-terminal phosphotyrosine interaction domain (PID) binds to the intracellular tail of the beta-amyloid precursor protein (betaPP), a protein of central importance to the pathogenesis of dementias of the Alzheimer type. To study the physiological functions of FE65, we generated a line of FE65 knockout mice via gene targeting. By Western analysis with a panel of FE65-specific antibodies, we demonstrate that the 97-kDa full-length FE65 (p97) was ablated in the mutant mice, and that a previously undescribed FE65 isoform with apparent molecular mass of 60 kDa (p60) was expressed in both wild-type and mutant mice. p60 had a truncated N-terminus and was likely to be generated through alternative translation. Expressions of the two isoforms appeared to be brain region distinct and age dependent. The p97FE65(-/-) mice were viable and showed no obvious physical impairments or histopathological abnormalities. However, p97FE65(-/-) and p97FE65(+/-) mice exhibited poorer performances than wild-type mice on a passive avoidance task when tested at 14 months (P <.05). p97FE65(-/-) mice at 14 months also exhibited impaired hidden-platform acquisition (P <.05) and a severe reversal-learning deficit (P <.002) but normal visual-platform acquisition in the Morris water maze tests. Probe trials confirmed impairments in p97FE65(-/-) mice in relearning of new spatial information, suggesting a hippocampus-dependent memory-extinction deficit. Reduced secretion of Abeta peptides was observed in primary neuronal cultures of hybrids of p97FE65(-/-)/betaPP transgenic (Tg2576) mice. These studies suggest an important and novel function of FE65 in learning and memory.

Topics: Aging; Amyloid beta-Peptides; Analysis of Variance; Animals; Animals, Newborn; Avoidance Learning; Behavior, Animal; Blotting, Northern; Blotting, Western; Brain; Cells, Cultured; Cerebral Cortex; Electroshock; Female; Indoles; Male; Maze Learning; Memory Disorders; Mice; Mice, Knockout; Molecular Structure; Motor Activity; Nerve Tissue Proteins; Nuclear Proteins; Peptide Fragments; Protein Isoforms; Psychomotor Performance; Reaction Time; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Swimming; Time Factors; Transfection; Vocalization, Animal

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

The authors investigated the effects of bilateral intrahippocampal co-injection of Abeta1-40 (4 microg for each side) with ibotenic acid (Ibo, 2 microg for each side) on rats' performance in the open field behavior, Y-maze, and passive avoidance task, and also examined some neurochemical changes in hippocampus two weeks after the co-injection. The results showed that the co-injection of Abeta1-40 with Ibo induced a decrease in exploratory activity and a significant decline in learning-memory ability of the tested rats (p < .01). The neurochemistry changes induced by the co-injection included a significant decreased in membrane fluidity of hippocampal mitochondria (p < .01), a significant decrease in the activity of SOD (p < .01), and a remarkable increase in the content of MDA (p < .01). These results suggest that the co-injection of Abeta1-40 with Ibo may induce an increase of hippocampal damage by peroxidation, and a serious learning and memory impairment of the rats. The results also suggest that the co-injection of Abeta1-40 with Ibo may provide a useful animal model for Alzheimer's disease (AD) research.

Topics: Amyloid beta-Peptides; Animals; Avoidance Learning; Disease Models, Animal; Exploratory Behavior; Hippocampus; Ibotenic Acid; Learning Disabilities; Male; Malondialdehyde; Maze Learning; Membrane Fluidity; Memory Disorders; Mitochondria; Peptide Fragments; Random Allocation; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

The amyloid pathology in Alzheimer's disease is accompanied by a chronic inflammatory response characterized by gliosis and activated microglial cells surrounding senile plaques. Epidemiological studies have shown nonsteroidal anti-inflammatory drug treatment reduces the risk of Alzheimer's disease. We have previously shown that injection of a combination of Abeta40 and Abeta43 in the dentate gyrus of the rat induces aggregated amyloid deposits and inflammation associated with dysfunctional synaptic plasticity and learning deficits. Here we characterize the effectiveness of nonsteroidal anti-inflammatory treatment in this model and show that this treatment restores the working memory deficit and decremental long-term potentiation in the dentate gyrus. Importantly, we observe no qualitative difference in the presence of aggregated material but a substantial reduction in microglial-induced inflammation, suggesting that mature aggregated plaques may not be directly responsible for the deficits but may trigger an inflammatory response which has a detrimental effect on synaptic function and memory.

Topics: Amyloid beta-Peptides; Animals; Cell Aggregation; Dentate Gyrus; Excitatory Postsynaptic Potentials; Indomethacin; Male; Memory Disorders; Neuronal Plasticity; Peptide Fragments; Rats; Rats, Sprague-Dawley

We compared beta-amyloid peptide (Abeta) levels in the serum, CSF and brain (hippocampus) and correlated these with spatial learning in APP+PS1 transgenic mice. Compared with non-transgenic littermates, male 14-month-old APP + PS1 mice were impaired in spatial learning in the water maze. Among the APP + PS1 mice, only the hippocampal insoluble Abeta42 level correlated with spatial memory (r = -0.44). The levels of insoluble Abeta40 and Abeta42 were highly correlated (r = 0.92), and also correlated with soluble hippocampal Abeta42 (r = 0.64/0.69), which further correlated with the CSF Abeta42 (r = 0.52). None of these parameters correlated with serum Abeta40 levels. These findings support the role of insoluble Abeta42 in memory dysfunction and suggest a model with several pools (insoluble, extracellular soluble, CSF) of Abeta being in partial equilibrium with each other.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Exploratory Behavior; Hippocampus; Humans; Male; Maze Learning; Membrane Proteins; Memory Disorders; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Presenilin-1; Reaction Time; Solubility

Chronic brain hypoperfusion (CBH) using permanent occlusion of both common carotid arteries in an aging rat model, has been shown to mimic human mild cognitive impairment (MCI), an acknowledged high risk condition that often converts to Alzheimer's disease. An aging rat model was used to determine whether hippocampal nitric oxide (NO) is abnormally expressed following CBH for two or eight weeks. At each time point, spatial memory was measured with the Morris water maze and hippocampal A beta 1-40/1-42 concentrations were obtained using sandwich ELISA. Real-time amperometric measures of NO representing the constitutive isoforms of neuronal nitric oxide synthase (nNOS) and endothelial (e)NOS were also taken at each time point to ascertain whether NO levels changed as a result of CBH, and if so, whether such NO changes preceded or followed any memory or amyloid-beta pathology. We found that two weeks after CBH, NO hippocampal levels were upregulated nearly four-fold when compared to nonoccluded rats but no alteration in spatial memory of A beta products were observed at this time point. By contrast, NO concentration had declined to control levels by eight weeks but spatial memory was found significantly impaired and A beta 1-40 (but not A beta 1-42) had increased in the CBH group when compared to control rats. Since changes in shear stress are known to upregulate eNOS but generally not nNOS, these results suggest that shear stress induced by CBH hyperactivated vascular NO derived from eNOS in the first two weeks as a reaction by the capillary endothelium to maintain homeostasis of local cerebral blood flow. The return of vascular NO to basal levels after eight weeks of CBH may have triggered metabolic changes within hippocampal cells resulting in hippocampal dysfunction as reflected by spatial memory impairment and by accumulation of A beta 1-40 peptide. In conclusion, our study shows that CBH initiates spatial memory loss in aging rats thus mimicking human MCI and also increases A beta 1-40 in the hippocampus. The memory and amyloid changes are preceded by NO upregulation in the hippocampus. These preliminary findings may be important in understanding, at least in part, the molecular mechanisms that precede memory impairment during chronic brain ischemia and as such, the pre-clinical stage leading to Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebrovascular Circulation; Cerebrovascular Disorders; Chronic Disease; Disease Models, Animal; Endothelium, Vascular; Hippocampus; Hypotension; Male; Maze Learning; Memory Disorders; Neurons; Nitric Oxide; Nitric Oxide Synthase; Peptide Fragments; Rats; Rats, Sprague-Dawley; Stress, Mechanical; Up-Regulation

Intraventricular infusion of rats with beta-amyloid for 14 days resulted in memory deficit in the water maze as well as decreases in choline acetyltransferase activities and somatostatin levels in the cerebral cortex and hippocampus. These changes were not altered by daily intraperitoneal injection of 20 mg/Kg melatonin. Orally administered Ginkgo biloba extract, however, partially reversed the memory deficit and the decrease in choline actyltransferase activities in the hippocampus. The latter treatment failed to reverse the decrease in somatostatin levels. The results indicate that orally administered Ginkgo biloba extract can protect the brain against beta-amyloid from changes leading to memory deficit through its effect on the cholinergic system.

Topics: Administration, Oral; Amyloid beta-Peptides; Animals; Antioxidants; Brain; Cerebral Cortex; Choline O-Acetyltransferase; Ginkgo biloba; Hippocampus; Injections, Intraperitoneal; Injections, Intraventricular; Male; Maze Learning; Melatonin; Memory Disorders; Peptide Fragments; Plant Extracts; Rats; Rats, Sprague-Dawley; Somatostatin

Two experiments are described assessing whether long-term intraventricular or intrahippocampal administration of beta-amyloid protein 1-40 (beta A1-40) affects spatial working memory in rats monitored in a longitudinal study using the open-field water maze. A delayed matching-to-position procedure (DMTP) was employed in which platform locations were semi-randomly altered between days but were kept constant over the four trials on each day. Intertrial intervals (ITIs) were either 30 s or 1 h between Trials 1 and 2 (all other intervals = 30 s), with Trial 2 performance being an index for spatial working memory. Animals were trained before and tested repeatedly at various intervals after application of various compounds (see below) in five successive test sessions (TSs). In Experiment 1, beta A1-40 was applied after a challenge with long-term oral exposure to aluminium (Al; as 0.1% sulfate in drinking water). This in itself did not affect spatial working memory at any delay, despite of the more than 6 months of intake. beta A1-40 administered alone via intracerebroventricular (icv) minipumps (20 micrograms in 250 microliters) led to a small increase in latencies to find the platform, which recovered to control levels 3 months after minipumps were exhausted. Application of beta A1-40 in Al-exposed animals led to a subtle and progressive decline in working memory. This deterioration was reversed by the nootropic compound nefiracetam, which had no effect on the Al only group. In Experiment 2, well-trained rats were bilaterally implanted with intra-hippocampal minipumps containing beta A1-40 or reverse sequence beta A40-1. This did not impair spatial working memory in the DMTP task, measured either directly after minipumps were exhausted, or 2 weeks later. When intraperitoneally (i.p.) injected with a low concentration of the muscarinic antagonist scopolamine (0.2 mg/kg), a dose that was not effective alone, animals in the beta A1-40 group were amnesic. These data suggest that intra-hippocampal beta A1-40 administration alters cholinergic transmission, but these alterations may be mild and thus do not lead to obvious working memory deficits in a DMTP task in well-trained animals.

Topics: Administration, Oral; Amyloid beta-Peptides; Animals; Female; Hippocampus; Injections, Intraventricular; Longitudinal Studies; Male; Maze Learning; Memory Disorders; Peptide Fragments; Rats

Signaling pathways underlying the cognitive deficit of the Alzheimer's disease (AD) are not completely understood. Protein kinase C (PKC), a major neuronal protein plays a critical role in cellular signal transduction and it is known to be subjected to modulation in AD. We showed previously that, chronic infusion of beta-amyloid (1-40) into rat cerebroventricle leads to deficit in spatial and non-spatial memory formation. As an attempt to identify the cellular correlates of the memory deficit, in the present study we investigated the PKC activation in different brain areas. Chronic infusion of beta-amyloid (1-40) for 14 days into the rat cerebroventricle decreased the activity of soluble protein kinase C (PKC) in the hippocampus. Subcellular translocation of PKC to membrane fraction in hippocampal slices of rats treated with beta-amyloid (1-40) was completely abolished under acute stimulation with 0.5 microM phorbol-dibutyrate (PDBu). We also reported a decreased affinity (k(D)) for PDBu binding in the hippocampus, cerebral cortex and striatum. The total number of binding sites for PDBu (B(max)) was increased, in the three brain areas analyzed on the day 14, but the changes were not statistically significant. Our data indicate that chronic accumulation of beta-amyloid (1-40) into the rat brain reduced activation of PKC, effect that would substantially contribute to the memory deficit found in these animals.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Binding Sites; Brain; Cell Membrane; Cerebral Cortex; Chronic Disease; Disease Models, Animal; Down-Regulation; Hippocampus; Injections, Intraventricular; Male; Memory Disorders; Neostriatum; Peptide Fragments; Phorbol 12,13-Dibutyrate; Protein Kinase C; Protein Transport; Rats; Rats, Wistar; Subcellular Fractions

We injected a combination of the beta-amyloids (Abetas) Abeta40 and Abeta43 to "seed" formation of amyloid deposits in the dorsal dentate gyrus of rats in vivo, on the basis of a theory of Jarrett and Landsbury (1993). Rats were tested on several different learning tasks, and synaptic transmission and plasticity were assessed in vivo. Between 7 and 16 weeks after injection, we found aggregated amyloid material, reactive astrocytosis, microgliosis, and cell loss around the sites of injection. Rats were impaired specifically in working memory type tasks in accordance with the type of memory deficit observed in the early stages of Alzheimer's disease. Synaptic transmission and long-term potentiation, a candidate cellular mechanism for memory, were severely impaired in vivo. Injections of the same dose of fragments individually did not induce these effects. These findings suggest that aggregated amyloid material induces cognitive deficits similar to those observed in the early phases of Alzheimer's disease via an alteration in neuronal transmission and plasticity.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Dentate Gyrus; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Postsynaptic Potentials; Hippocampus; Long-Term Potentiation; Male; Maze Learning; Memory Disorders; Memory, Short-Term; Microinjections; Neuronal Plasticity; Peptide Fragments; Plaque, Amyloid; Rats; Rats, Sprague-Dawley; Rats, Wistar; Synaptic Transmission

Topics: Acetylcholine; Amyloid beta-Peptides; Animals; Cerebral Ventricles; Chemotherapy, Cancer, Regional Perfusion; Cholinergic Agents; Guanidines; Hippocampus; Memory Disorders; Microglia; Models, Biological; Nicotine; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peptide Fragments; Rats

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

The amyloid precursor protein undergoes proteolysis at several sites to yield a number of functionally relevant peptides, including beta-amyloid and the soluble amyloid precursor protein derivatives alpha-soluble amyloid precursor protein and beta-soluble amyloid precursor protein. beta-Amyloid is the primary constituent of senile plaques associated with Alzheimer's disease, while a-soluble amyloid precursor protein promotes synaptogenesis and plays a role in neuroprotective processes. We tested for age-related alterations in these amyloid precursor protein proteolytically derived peptides by measuring the levels of alpha-soluble amyloid precursor protein, total soluble amyloid precursor proteins (alpha- and beta-soluble amyloid precursor protein combined) and beta-amyloid in cerebrospinal fluid from three-, 13- and 23-month-old Fischer-344 rats. Western blot analysis using selective antibodies revealed 50% less total soluble amyloid precursor protein and a-soluble amyloid precursor protein in cisternal cerebrospinal fluid from 23-month-old rats compared with three- and 13-month-old animals. Mass spectrometric analysis indicated, however, that beta-amyloid in cerebrospinal fluid was not different between the three age groups. In a second group of young (five to six months of age) and aged (24-25 months of age) rats, spatial working and reference memory were assessed in a water maze followed by collection of cerebrospinal fluid. As a group, the aged rats consistently performed below the young rats in both working and reference memory tests. The aged rats also had 49% less cerebrospinal fluid alpha-soluble amyloid precursor protein than did their younger counterparts. There was a positive correlation (r= 0.52-0.57, P < 0.001) between performance in spatial memory tasks and cerebrospinal fluid alpha-soluble amyloid precursor protein in these young and aged rats. These results suggest that there is a positive association between cerebrospinal fluid levels of alpha-soluble amyloid precursor protein and cognitive performance in rats, and that alpha-soluble amyloid precursor protein may be involved in the spatial learning and memory changes that accompany ageing.

Topics: Aging; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Cerebral Cortex; Cognition; Conditioning, Psychological; Endopeptidases; Hippocampus; Male; Maze Learning; Memory Disorders; Peptide Fragments; Rats; Rats, Inbred F344; Retention, Psychology; Solubility; Space Perception; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Visual Acuity

1 In the present study, we examined whether deprivation of oestrogens by ovariectomy could modify learning and memory deficits caused by a continuous intracerebroventricular (i.c.v.) infusion of amyloid beta-peptide (Abeta), the major constituent of senile plaques in AD. 2 Neither long-term (3 months) nor short-term (1 month), deprivation of oestrogens by ovariectomy caused a significant impairment in spatial learning and memory in a water maze and spontaneous alternation behaviour in a Y-maze. 3 A continuous i.c.v. infusion of Abeta-(1-42) caused spatial learning and memory deficits in both ovariectomized and sham-operated rats. 4 The Abeta-induced working memory deficits were significantly potentiated in ovariectomized rats compared with sham-operated rats when mnemonic ability was examined 3 months after ovariectomy. 5 These results suggest that long-term deprivation of oestrogens induced by ovariectomy increases susceptibility to memory deficits produced by Abeta-(1-42) in rats.

Topics: Amyloid beta-Peptides; Animals; Body Weight; Estradiol; Estrogens; Female; Follicle Stimulating Hormone; Injections, Intraventricular; Maze Learning; Memory Disorders; Memory, Short-Term; Motor Activity; Ovariectomy; Peptide Fragments; Rats; Rats, Wistar

We have reported that the continuous infusion of beta-amyloid protein-(1-40) into the rat cerebral ventricle produces learning and memory deficits accompanied by dysfunction in the cholinergic and dopaminergic systems. L-Pyroglutamyl-L-asparaginyl-L-seryl-L-prolyl-L-arginylglycinamide (NC-1900), an active fragment analog of arginine vasopressin in the rat brain, is a stable peptide with a five-fold longer half-life than that of arginine vasopressin-(4-9). In the present study, we examined the effects of NC-1900 on learning and memory deficits in beta-amyloid protein-(1-40)-infused rats. The rats were injected subcutaneously with NC-1900 (0.1 and 1 ng kg(-1)) once a day throughout the period of behavioral examination. In the beta-amyloid protein-infused rats, learning and memory in water maze and passive avoidance tasks were impaired compared with these in the control rats. NC-1900 prevented the learning and memory deficits in beta-amyloid protein-infused rats. Moreover, NC-1900 tended to increase the choline acetyltransferase activity in the frontal cortex of the beta-amyloid protein-infused rats. These results suggested that NC-1900 could be useful for the treatment of patients with Alzheimer's disease.

Topics: Amyloid beta-Peptides; Animals; Arginine Vasopressin; Behavior, Animal; Choline O-Acetyltransferase; Frontal Lobe; Hippocampus; Injections, Intraventricular; Learning Disabilities; Male; Memory Disorders; Oligopeptides; Peptide Fragments; Pyrrolidonecarboxylic Acid; Rats; Rats, Wistar

Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta-amyloid (Abeta) precursor protein containing a Lys670 --> Asn, Met671 --> Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Abeta(1-40) and a 14-fold increase in Abeta(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Abeta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Abeta. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Brain Chemistry; Learning Disabilities; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Peptide Fragments; Psychomotor Performance

Alzheimer's disease (AD) is characterized by the presence of senile plaques. The core of the plaque consists of beta-amyloid protein. In AD patients, learning and memory are impaired with a concomitant loss of the cholinergic marker enzyme, choline acetyltransferase (ChAT). However, direct evidence that beta-amyloid protein is related to the impairment of learning and memory has not been demonstrated. In this study, we investigated whether memory impairment and neuronal dysfunction were produced after 2 weeks continuous infusion of beta-amyloid protein (3, 30 and 300 pmol/day) into the cerebral ventricles in adult rats. To investigate the ability of learning and memory in beta-amyloid protein-treated rats, water maze and passive avoidance tasks were carried out. The performance of both tasks in beta-amyloid protein-treated rats was impaired. ChAT activity in the frontal cortex (3 and 30 pmol/day) and hippocampus (300 pmol/day) significantly decreased. These results suggest that beta-amyloid protein is related to the impairment of learning and memory, and neurodegeneration, and that beta-amyloid protein-treated rats could be used as an animal model for AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Avoidance Learning; Brain Chemistry; Choline O-Acetyltransferase; Corpus Striatum; Disease Models, Animal; Frontal Lobe; Hippocampus; Infusion Pumps, Implantable; Injections, Intraventricular; Learning Disabilities; Male; Maze Learning; Memory Disorders; Nerve Tissue Proteins; Parietal Lobe; Peptide Fragments; Rats; Rats, Wistar