Sleep, Pericytes, and Alzheimer's Disease

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Abstract This proposal responds to the NIH High-Priority Research Topics announcements for PAR-19-070: mechanism underlying the vascular risk, sleep efficiency, and chronic circadian disruption in the etiology of Alzheimer's disease (AD). We are a research group focusing on the brain circuitry of sleep disorder narcolepsy (caused by loss of the hypothalamic wake-promoting orexin neurons). By following the emerging scientific evidence on the protective effects of sleep for AD, we propose investigating the intrinsic mechanism involved. Pericytes, a type of mural cells of the capillary and a key component of the neurovascular unit (NVU), become our focus because of their unique function in regulating cerebral blood flow (CBF) and the blood-brain barrier (BBB) permeability. Strong evidence suggests that pericytes malfunction or degeneration contributes to AD pathology by affecting CBF and breaking down BBB. Intriguingly, similar mechanisms also underlie the contribution of sleep loss to AD pathology. Thus, we ask whether pericytes are the mediator between sleep and AD pathology. Improving sleep might delay AD pathogenesis by protecting pericytes and maintaining BBB integrity. It is the first time that brain pericytes are studied in the framework of sleep and AD. Recent advances in pericyte research and our latest preliminary data show the feasibility of the approach. This project will have confirmed the functional correlations among pericytes, sleep, and AD pathogenesis at the end of the funding period and provided valuable evidence for future pericytes-based therapies for AD and sleep disorders.