Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer’s Disease Mouse Model
Affiliations: [a] Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School Medicine, Springfield, Illinois, USA | [b] Department of Pharmacology, Southern Illinois University School Medicine, Springfield, Illinois, USA | [c] Department of Neurology, Southern Illinois University School Medicine, Springfield, Illinois, USA | [d] Institute for Memory Impairment and Neurological Disorders (MIND), Department of Biomedical Engineering, University of California Irvine, Irvine, California, USA (current)
Correspondence:
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Correspondence to: Gregory J. Brewer, Department of Biomedical Engineering, Institute for Memory Impairment and Neurological Disorders (MIND), Nat Sci, 2, Rm 3101, University ofCalifornia Irvine, Irvine, California 92697-2715, USA. Tel.: +1 217 502 4511; Fax: +1 949 824 1727; E-mail: [email protected]
Abstract: It is unclear whether pre-symptomatic Alzheimer’s disease (AD) causes circadian disruption or whether circadian disruption accelerates AD pathogenesis. In order to examine the sensitivity of learning and memory to circadian disruption, we altered normal lighting phases by an 8 h shortening of the dark period every 3 days (jet lag) in the APPSwDI NOS2–/– model of AD (AD-Tg) at a young age (4-5 months), when memory is not yet affected compared to non-transgenic (non-Tg) mice. Analysis of activity in 12-12 h lighting or constant darkness showed only minor differences between AD-Tg and non-Tg mice. Jet lag greatly reduced activity in both genotypes during the normal dark time. Learning on the Morris water maze was significantly impaired only in the AD-Tg mice exposed to jet lag. However, memory 3 days after training was impaired in both genotypes. Jet lag caused a decrease of glutathione (GSH) levels that tended to be more pronounced in AD-Tg than in non-Tg brains and an associated increase in NADH levels in both genotypes. Lower brain GSH levels after jet lag correlated with poor performance on the maze. These data indicate that the combination of the environmental stress of circadian disruption together with latent stress of the mutant amyloid and NOS2 knockout contributes to cognitive deficits that correlate with lower GSH levels.
