Amelioration of social isolation-triggered onset of early Alzheimer's disease-related cognitive deficit by N-acetylcysteine in a transgenic mouse model.
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.
Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan 701, Taiwan.
Ya-Hsin
YH
Hsiao
Jinn-Rung
JR
Kuo
Shun-Hua
SH
Chen
Po-Wu
PW
Gean
D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001703:Biophysics; D019921:Biotinylation; D002154:Calpain / Q000378:metabolism; D002461:Cell Line, Transformed; D003072:Cognition Disorders / Q000209:etiology* / Q000517:prevention & control*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004797:Enzyme-Linked Immunosorbent Assay; D005239:Fear / Q000523:psychology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012934:Social Isolation / Q000523:psychology*; D013997:Time Factors; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018094:Receptors, Metabotropic Glutamate; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C108822:metabotropic glutamate receptor 2; C104077:metabotropic glutamate receptor type 1; D051360:Cyclin-Dependent Kinase 5; D051745:Protein Kinase C-delta; D002154:Calpain; D000111:Acetylcysteine