amyloid-beta-peptides and Learning-Disabilities

This study assessed whether administering porcine brain hydrolysate (PBH) ameliorates the impairment of spatial cognition learning ability in amyloid β (Aβ)-infused rats. PBH was prepared using organic solvents (i.e., acetone and ethanol). Enzyme hydrolysates were derived from these PBH and the sequence of the Aβ peptide for infusion was selected. The results indicated the PBH, in particular EP (porcine brain extract with ethanol and protease N), demonstrated the potentials to reduce damage of neurodegenerative disorders in vitro and in vivo. The principal findings of this study indicate that PBH has prolyl endopeptidase inhibitory activity in vitro. Moreover, administering EP to Aβ(1-40)-infused rats significantly improves their performance on reference, spatial performance, and working memory tests during water maze tasks; concurrent proportional decreases are also observed in malondialdehyde levels, acetylcholinesterase (AChE) activity, and Aβ accumulation levels in brain tissues. The PBH was suggested to ameliorate learning deficits associated with Alzheimer's disease by inhibition of lipid peroxidation in the brain of Aβ infused rat.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Brain Chemistry; Enzyme Inhibitors; Learning Disabilities; Lipid Peroxidation; Male; Malondialdehyde; Maze Learning; Memory, Short-Term; Peptide Fragments; Prolyl Oligopeptidases; Rats, Wistar; Serine Endopeptidases; Spatial Learning; Swine; Tissue Extracts

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

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

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

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

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

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

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

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

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

We evaluated the effects of 1-(3',4'-dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a new gamma-secretase modulator, on brain beta-amyloid pathology and spatial memory in transgenic mice expressing the Swedish and London mutations of human amyloid precursor protein (hAPP).. Sixty 6-month-old hAPP mice were treated for 6 months with CHF5074 or ibuprofen (375 ppm in the diet) or standard diet. Twenty-one wild-type mice received standard diet.. Compared with transgenic controls, CHF5074 treatment significantly reduced the area occupied by plaques in cortex (P = 0.003) and hippocampus (P = 0.004). The number of plaques were also reduced by CHF5074 in both cortex (P = 0.022) and hippocampus (P = 0.005). Plaque-associated microglia in CHF5074-treated animals was lower than in transgenic controls in cortex (P = 0.008) and hippocampus (P = 0.002). Ibuprofen treatment significantly reduced microglia area in cortex and hippocampus but not beta-amyloid burden. On the last day of the Morris water maze, transgenic controls performed significantly worse than the non-transgenic animals and the CHF5074-treated transgenic mice, on the swimming path to reach the hidden platform. Ibuprofen-treated animals did not perform significantly better than transgenic controls.. Chronic CHF5074 treatment reduced brain beta-amyloid burden, associated microglia inflammation and attenuated spatial memory deficit in hAPP mice. This novel gamma-secretase modulator is a promising therapeutic agent for Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Brain; Cyclopropanes; Flurbiprofen; Humans; Ibuprofen; Learning Disabilities; Memory; Mice; Mice, Transgenic; Microglia; Mutation; Peptide Fragments; Plaque, Amyloid

To examine the effects of soft-diet feeding on the dopaminergic system in a model rat for Alzheimer's disease (AD), we measured dopamine release in the hippocampus using a microdialysis approach and assessed learning ability and memory using step-through passive avoidance tests. Furthermore, we immunohistochemically examined the ventral tegmental area (VTA), which is the origin of hippocampal dopaminergic fibers using tyrosine hydroxylase (TH), a marker enzyme for the dopaminergic nervous system. Feeding a soft diet decreased dopamine release in the hippocampus and impaired learning ability and memory in AD model rats in comparison with rats fed a hard diet; however, TH-immunopositive profiles in the VTA seemed not to be notably different between rats fed a soft diet and those fed a hard diet. These observations suggest that soft-diet feeding enhances the impairment of learning ability and memory through the decline of dopamine release in the hippocampus in AD rats.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Avoidance Learning; Diet; Disease Models, Animal; Dopamine; Electrochemistry; Hippocampus; Learning Disabilities; Male; Microdialysis; Peptide Fragments; Rats; Reaction Time; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline due to neuronal loss and neural network dysfunction. It has been postulated that progressive neuronal loss in AD is consequence of the neurotoxic properties of the amyloid-beta peptide (Abeta). In the present study, we investigated the effect of T-817MA (1-{3-[2-(1-benzothiophen-5-yl)ethoxy] propyl}-3-azetidinol maleate), a newly synthesized neurotrophic compound, on place learning deficits in rats with hippocampal damages. To induce granule cell loss in the dentate gyrus (DG) of the hippocampus, Abeta (1-40) was continuously infused (300 pmol/day) into the cerebral ventricle using a mini-osmotic pump for 5 weeks. Three weeks after the Abeta infusion, the rats were tested in a place learning task, which required them to alternatively visit two diametrically opposed areas in an open field to obtain intracranial self-stimulation reward. The results indicated that the Abeta-infused rats without treatment of T-817MA displayed learning impairment in the task; their performance level was significantly inferior to that of the vehicle rats. Treatment of T-817MA (8.4 mg/kg/day, p.o.) significantly improved the task performance of the Abeta-infused rats. Furthermore, T-817MA prevented granule cell loss due to Abeta-infusion, which was correlated to task performance of the rats. However, other cognitive enhancer, an acetylcholinesterase inhibitor, had no such effects. The results demonstrated that T-817MA ameliorated learning deficits induced by Abeta infusion, which might be attributed to neuroprotection in the hippocampus.

Topics: Amyloid beta-Peptides; Animals; Beclomethasone; Behavior, Animal; Conditioning, Operant; Dose-Response Relationship, Drug; Drug Interactions; Hippocampus; Learning Disabilities; Male; Maleates; Movement; Neuroprotective Agents; Peptide Fragments; Rats; Rats, Wistar; Self Administration; Thiophenes; Time Factors

We have previously shown that intracerebroventricular (i.c.v.) infusion of amyloid-beta (Abeta)1-40 produces oxidative stress and cholinergic dysfunction, as well as learning and memory deficits, in rats. In the present study, effects of a newly synthesized azaindolizinone derivative, spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446), were assessed in rats with learning deficits induced by Abeta1-40 or scopolamine. The i.c.v. infusion of Abeta1-40 caused impairments in spontaneous alternation behavior in a Y-maze task, spatial reference and short-term memory in a water-maze task, and retention of passive-avoidance learning. Abeta1-40-infused rats also showed reduction in choline acetyltransferase (ChAT) activity in the medial septum and hippocampus, but not in the basal forebrain and cortex, and a decrease in glutathione S-transferase (GST)-like immunoreactivity in the cortex. Nicotine-stimulated acetylcholine (ACh) release in Abeta1-40-infused rats was lower than that in vehicle-infused rats. Oral administration of ZSET1446 at the dose range of 0.01 to 1 mg/kg ameliorated Abeta1-40-induced learning impairment in Y-maze, water-maze, and passive-avoidance tasks. ZSET1446 reversed the decrease of ChAT activity in the medial septum and hippocampus, GST-like immunoreactivity in the cortex, and nicotine-stimulated ACh release of Abeta1-40-treated rats to the levels of vehicle-infused control rats. Furthermore, 0.001 to 0.1 mg/kg ZSET1446 showed ameliorative effects on learning impairments caused by scopolamine in a passive-avoidance task. These results suggest that ZSET1446 may be a potential candidate for development as a therapeutic agent to manage cognitive impairment associated with conditions such as Alzheimer's disease.

Topics: Administration, Oral; Amyloid beta-Peptides; Animals; Behavior, Animal; Blotting, Western; Brain; Choline O-Acetyltransferase; Cognition; Indans; Injections, Intraventricular; Learning Disabilities; Male; Maze Learning; Memory; Motor Activity; Peptide Fragments; Rats; Rats, Wistar; Scopolamine; Spiro Compounds

In the present study, we investigated the relationship between the docosahexaenoic acid (DHA)-induced protection of learning deficit of amyloid beta(1-40)-infused Alzheimer's disease (AD) model rats and changes in synaptosomal plasma membrane fluidity of the cerebral cortex. Synaptosomal membrane lateral and rotational fluidity were measured using pyrene excimer spectroscopy and fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH), respectively. Avoidance learning ability, as assessed by a two-way active avoidance paradigm, decreased significantly in the AD model rats. Pyrene-determined annular/non-annular fluidity ratio and the DPH-determined bulk fluidity of the synaptosomal plasma membrane decreased in the amyloid beta(1-40)-infused rats. Oral pre-administration of DHA (300 mg/kg per day for 12 weeks) significantly increased both lateral and rotational fluidity. The synaptosomal membrane DHA content increased and the cholesterol to phospholipid molar ratio and lipid peroxidation decreased. The annular to non-annular fluidity ratio of the synaptic plasma membrane was positively correlated with total avoidance learning. The present results indicate that DHA-induced alterations in synaptic plasma membrane fluidity may contribute to the synaptic plasma membrane-related functions that constitute avoidance learning-related memory in amyloid beta(1-40)-infused rats.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Avoidance Learning; Docosahexaenoic Acids; Learning; Learning Disabilities; Lipid Bilayers; Lipid Peroxidation; Male; Membrane Fluidity; Membrane Lipids; Models, Biological; Models, Theoretical; Peptide Fragments; Rats; Rats, Wistar; Synaptic Membranes

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 nicotinic (nAChRs) and muscarinic (mAChRs) acetylcholine receptors and acetylcholinesterase (AChE) activity were studied in the brains of APP(SWE) transgenic mice (Tg+) and age-matched nontransgenic controls (Tg-) that were between 4 and 19 months of age. A significant increase in the binding of 125I-labeled alpha-bungarotoxin (alpha7 nAChRs) was observed in most brain regions analyzed in 4-month-old Tg+ mice, preceding learning and memory impairments and amyloid-beta (Abeta) pathology. The enhanced alpha7 receptor binding was still detectable at 17-19 months of age. Increase in [3H]cytisine binding (alpha4beta2 nAChRs) was measured at 17-19 months of age in Tg+ mice, at the same age when the animals showed heavy Abeta pathology. No significant changes in [3H]pirenzepine (M1 mAChRs) or [3H]AFDX 384 (M2 mAChRs) binding sites were found at any age studied. The upregulation of the nAChRs probably reflects compensatory mechanisms in response to Abeta burden in the brains of Tg+ mice.

Topics: Acetylcholinesterase; alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Binding Sites; Brain; Disease Models, Animal; Female; Learning Disabilities; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Peptide Fragments; Plaque, Amyloid; Radioligand Assay; Receptors, Muscarinic; Receptors, Nicotinic; RNA, Messenger; Up-Regulation

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