Sleep and Diurnal Rest-Activity Rhythm Disturbances in a Mouse Model of Alzheimer’s Disease

Study Objectives Accumulating evidence suggests a strong association between sleep, amyloid-beta (Aβ) deposition, and Alzheimer’s disease (AD). We sought to determine if: (1) deficits in rest-activity rhythms and sleep are significant phenotypes in J20 AD mice, (2) metabotropic glutamate receptor 5 inhibitors (mGluR 5 ) could rescue deficits in rest-activity rhythms and sleep, and (3) Aβ levels are responsive to treatment with mGluR 5 inhibitors. Methods Diurnal rest-activity levels were measured by actigraphy and sleep-wake patterns by electroencephalography (EEG), while animals were chronically treated with mGluR 5 inhibitors. Behavioral tests were performed, and Aβ levels measured in brain lysates. Results J20 mice exhibited a 4.5 hour delay in the acrophase of activity levels compared to wild-type littermates, and spent less time in REM sleep during the second half of the light period. J20 mice also exhibited decreased NREM delta power but increased NREM sigma power. The mGluR 5 inhibitor CTEP rescued the REM sleep deficit and improved NREM delta and sigma power but did not correct rest-activity rhythms. No statistically significant differences were observed in Aβ levels, rotarod performance or the passive avoidance task following chronic mGluR 5 inhibitor treatment. Conclusions J20 mice have disruptions in rest-activity rhythms and reduced homeostatic sleep pressure (reduced NREM delta power). NREM delta power was increased following treatment with an mGluR 5 inhibitor. Drug bioavailability was poor. Further work is necessary to determine if mGluR 5 is a viable target for treating sleep phenotypes in AD. Statement of Significance Sleep disruption is evolving as an important risk factor as well as phenotype of neurological diseases including Alzheimer’s disease. This study is novel in determining alterations in the rest-activity rhythm and sleep-wake pattern of J20 Alzheimer’s disease mice and wild type littermates. Specifically, there is a delay in acrophase with prolonged hyperactivity during the dark cycle, and reduced sleep pressure that was improved by treatment with mGluR 5 inhibitor. Critical remaining knowledge gaps and future directions include testing the effects of Alzheimer’s disease drugs on rescue of sleep and rest-activity patterns in other Alzheimer’s disease models. These studies are relevant to human Alzheimer’s disease as monitoring sleep phenotypes may predict disease risk, and therapies that normalize sleep patterns may slow progression.