Abstract
Epidemiological study reveals that socially isolated persons have increased risk of developing Alzheimer's disease (AD). Whether this risk arises from an oxidative stress is unclear. Here we show that N-acetylcysteine (NAC), an anti-oxidant, is capable of preventing social isolation-induced accelerated impairment of contextual fear memory and rundown of hippocampal LTP in 3-month old APP/PS1 mice. Increased hippocampal levels of γ-secretase activity, Aβ-40 and Aβ-42 seen in the isolated APP/PS1 mice were reduced by chronic treatment of NAC. In addition, social isolation-induced increase in calpain activity and p25/p35 ratio concomitant with decrease in membrane-associated p35 and p35/Cdk5 activity was normalized by NAC. NAC pretreatment also reversed isolation-induced decrease in GluR1 Ser831 phosphorylation, surface expression of AMPARs and p35-GluR1-CaMKII interactions. These results suggest that NAC decreases γ-secretase activity resulting in the attenuation of Aβ production, calpain activity and conversion of p35 to p25 which stabilized p35-GluR1-CaMKII interactions and restored GluR1 and GluR2 surface expression. Our results indicate that NAC is effective in mouse models of AD and has translation potential for the human disorder.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / pharmacology
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Acetylcysteine / therapeutic use*
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Alzheimer Disease / complications*
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Alzheimer Disease / genetics
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / genetics
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Analysis of Variance
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Animals
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Antioxidants / pharmacology
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Antioxidants / therapeutic use*
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Biophysics
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Biotinylation
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Calpain / metabolism
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Cell Line, Transformed
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Cognition Disorders / etiology*
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Cognition Disorders / prevention & control*
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Conditioning, Psychological / drug effects
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Conditioning, Psychological / physiology
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Cyclin-Dependent Kinase 5 / metabolism
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Electric Stimulation
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Enzyme-Linked Immunosorbent Assay
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Fear / psychology
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Hippocampus / drug effects
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Hippocampus / pathology
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Humans
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In Vitro Techniques
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Long-Term Potentiation / drug effects
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Long-Term Potentiation / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Patch-Clamp Techniques
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Peptide Fragments / metabolism
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Presenilin-1 / genetics
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Protein Kinase C-delta / genetics
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Protein Kinase C-delta / metabolism
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RNA, Messenger / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, Metabotropic Glutamate / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Social Isolation / psychology*
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Time Factors
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Transfection
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Antioxidants
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PSEN1 protein, human
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Peptide Fragments
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Presenilin-1
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RNA, Messenger
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RNA, Small Interfering
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Receptors, Metabotropic Glutamate
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)
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metabotropic glutamate receptor 2
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metabotropic glutamate receptor type 1
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Cyclin-Dependent Kinase 5
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Protein Kinase C-delta
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Calpain
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Acetylcysteine