PROJECT SUMMARY Sleep and Circadian Rhythms in Alzhiemer’s Disease: Potential bi-directional relationship with tau Sleep and circadian rhythm disturbances have long been described in symptomatic Alzheimer’s Disease (AD). Recent studies by our group and others show that these disturbances are detectable years before the onset of cognitive impairment, during the preclinical phase of AD. Our group has shown that modulating the amount of sleep in mice has striking effects on amyloid plaque deposition, as sleep deprivation augments plaque burden while sleep enhancement reduces plaques. Moreover, we have found that levels of Aβ peptide in the interstitial fluid (ISF) exhibit clear diurnal rhythms which are regulated by the sleep/wake cycle and the central circadian clock, and that disruption of the circadian system and promotes amyloid plaque formation. While amyloid plaque deposition is the first known biomarker change in AD, it appears to be the ability of amyloid plaques to augment tau aggregation and spreading that is directly linked to neurodegeneration and cognitive decline in AD. Tau spreading though the brain, and the effect of Aβ pathology on tau aggregation, can be modeled by injection of tau-enriched AD brain lysate into the brain of Aβ plaque-bearing APP knock-in mice. Based on our preliminary data, we hypothesize that sleep disturbance and circadian rhythm disruption may promote tau spreading and aggregation by increasing the release of tau seeding species from neurons. We propose to examine the impact of chronically restricting or increasing sleep on neuronal tau spreading and plaque-induced tau aggregation in mice. Because apolipoprotein E (apoE) strongly influence Aβ and tau pathology and interacts with sleep, we will elucidate the interaction between APOE genotype, sleep deprivation, and tau spreading and aggregation. Using both genetic and environmental circadian disruption models, we will perform similar experiments to determine the effects of circadian disruption on tau spreading and Aβ-induced tau aggregation, and explore the interplay between circadian disruption, sleep, and apoE on Aβ and tau pathology. Finally, we will examine the longitudinal relationship between sleep disturbance, circadian fragmentation, and preclinical Aβ and tau pathology in humans. We hypothesize a bidirectional relationship between AD pathology and sleep/circadian rhythms, in which AD pathology disrupts sleep/circadian function, while sleep/circadian disruption promotes AD pathology. We will if sleep or circadian rhythm changes are associated with increased future risk of plaque deposition, tau aggregation, or cognitive decline in humans. These studies will elucidate the interaction between sleep, circadian rhythms, and tau aggregation in mice and humans, as well as the role of apoE in that process.

PROJECT NARRATIVE Sleep disturbance and disruption of normal 24-hour bodily rhythms, known as circadian rhythms, are common symptoms of Alzheimer’s Disease. These changes can be detected years before memory loss begins. In mouse models and humans, we will determine how sleep loss or circadian rhythms affect tau, a protein which causes brain degeneration in Alzheimer’s Disease. By understanding how sleep and circadian rhythm problems contribute to Alzheimer’s Disease, we hope to design new preventative therapies for the disease.