Sleep, Pericytes, and Alzheimer's Disease

摘要 该提案响应了NIH关于PAR-19-070的高优先级研究主题公告： 血管风险、睡眠效率和慢性昼夜节律紊乱在糖尿病病因中的潜在机制 阿尔茨海默病(AD)。我们是一个专注于睡眠障碍发作性睡病的大脑回路的研究小组 (由下丘脑促进觉醒的增食欲素神经元丢失引起)。通过跟踪新兴的科学 关于睡眠对阿尔茨海默病的保护作用的证据，我们建议研究其内在机制。 周细胞是毛细血管的一种壁细胞，也是神经血管单位(NVU)的关键组成部分。 我们之所以关注它们，是因为它们在调节脑血流量和血脑屏障方面具有独特的功能 (Bbb)渗透性。强有力的证据表明，周细胞功能障碍或变性与AD有关 通过影响脑血流量和分解血脑屏障的病理改变。耐人寻味的是，类似的机制也是 睡眠不足在AD病理中的作用。因此，我们问周细胞是否是睡眠之间的中介。 和AD病理学。改善睡眠可能通过保护周细胞和维持血脑屏障延缓AD的发病 正直。这是首次在睡眠和阿尔茨海默病的框架下研究脑周细胞。最新进展 在周细胞研究中，我们最新的初步数据表明了该方法的可行性。这个项目将会有 在资助结束时确认了周细胞、睡眠和AD发病机制之间的功能相关性 该研究为未来以周细胞为基础的阿尔茨海默病和睡眠障碍治疗提供了宝贵的证据。

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.