Sleep, Pericytes, and Alzheimer's Disease

睡眠、周细胞和阿尔茨海默病

• 批准号: 10448572
• 负责人: Meng Liu
• 金额: $ 195.5万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448572
• 关键词: APP-PS1; Abeta clearance; Acute; Adopted; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid beta-Protein; Apoptosis; Area; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood flow; Brain; Calcium; Cells; Cerebrovascular Circulation; Characteristics; Chronic; Circadian Dysregulation; Cognitive deficits; Consumption; Contracts; Data; Development; Early Intervention; Energy Supply; Etiology; FDA approved; Focus Groups; Funding; Future; Goals; Hypothalamic structure; Image; Imaging Device; Lasers; Lateral; Length; Mediator of activation protein; Microcirculation; Mus; Narcolepsy; Neurons; Neuropeptides; Nutrient; Opsin; Oxygen; Pathogenesis; Pathology; Pattern; Pericytes; Pharmaceutical Preparations; Platelet-Derived Growth Factor beta Receptor; Prefrontal Cortex; Preoptic Areas; Process; Regulation; Research; Research Personnel; Research Priority; Risk; Role; Senile Plaques; Sleep; Sleep Deprivation; Sleep Disorders; Sleeplessness; Slow-Wave Sleep; Surface; Testing; Time; Transgenic Animals; United States National Institutes of Health; aged; animal breeding; antagonist; base; blood perfusion; blood-brain barrier permeabilization; brain circuitry; cranium; density; driving force; hemodynamics; hypocretin; imaging system; improved; in vivo; locus ceruleus structure; midbrain central gray substance; model design; mouse model; multidisciplinary; neuronal cell body; neurovascular coupling; neurovascular unit; non rapid eye movement; non-invasive imaging; novel; optogenetics; protective effect; receptor; relating to nervous system; response; sensor; tool

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.

摘要 本提案响应了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的病因学机制 阿尔茨海默病（AD）。我们是一个专注于睡眠障碍嗜睡症的大脑回路的研究小组 （由下丘脑唤醒促进食欲素神经元的损失引起）。通过跟踪新兴的科学 睡眠对AD的保护作用的证据，我们建议调查所涉及的内在机制。 周细胞是一种毛细血管壁细胞，是神经血管单位（NVU）的关键组成部分， 由于它们在调节脑血流和血脑屏障方面的独特功能， (BBB)磁导率强有力的证据表明，周细胞功能障碍或变性有助于AD 通过影响脑血流和破坏血脑屏障而病理学改变。有趣的是，类似的机制也构成了 睡眠缺失对AD病理学的贡献。因此，我们问周细胞是否是睡眠之间的中介 AD病理学改善睡眠可能通过保护周细胞和维持血脑屏障而延缓AD的发病 完整这是首次在睡眠和AD的框架下研究脑周细胞。最新进展 在周细胞的研究和我们最新的初步数据表明，该方法的可行性。该项目将有 证实了周细胞，睡眠和AD发病机制之间的功能相关性 为今后以周细胞为基础的AD和睡眠障碍治疗提供了有价值的证据。