Sleep Fragmentation and Alzheimer’s Disease

睡眠碎片化与阿尔茨海默病

• 批准号: 10219957
• 负责人: ADAM D BACHSTETTER
• 金额: $ 75.23万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10219957
• 关键词: APP-PS1; Abeta clearance; Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Anti-Inflammatory Agents; Astrocytes; Attenuated; Biological; Brain; Chronic; Cognition; Cognitive deficits; Correlative Study; Dementia; Demographic Factors; Deposition; Development; Disease; Disease Progression; Exhibits; Family; Frequencies; Human; Impaired cognition; Impairment; Inflammation; Knock-in; Knock-in Mouse; Life; Life Style; Light; Link; Mediating; Mediator of activation protein; Medical History; Microglia; Modeling; Moods; Mus; Nerve Degeneration; Noise; Pathology; Personal Satisfaction; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Process; Rest; Risk; Role; Schedule; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Slow-Wave Sleep; Societies; Synapses; System; Temperature; Testing; Time; Work; abeta accumulation; age related; beta amyloid pathology; circadian; circadian pacemaker; design; improved; middle age; mild cognitive impairment; mouse model; neuroinflammation; neuropathology; neurotoxic; novel; novel strategies; novel therapeutic intervention; pre-clinical; prevent; response; sleep quality; sleep quantity

Chronic sleep disruption, resulting from work schedules, noise exposure, family obligations, sleep disorders, or lifestyle choices, is a pervasive feature of contemporary life. Sleep problems affect up to 40% of AD patients, may precede cognitive impairments by more than a decade, and worsen as the disease progresses. As well as affecting mood and well-being, sleep disruption may drive the development of AD neuropathology for instance, by reducing clearance of amyloid-β (Aβ) and by promoting a neurotoxic proinflammatory state involving astrocytes and microglia. Sleep disruption can include reduced total sleep (sleep restriction [SR]), loss of deep sleep (also known as slow-wave sleep [SWS], marked by large amplitude, low frequency electrical activity), and fragmentation of sleep (SF) into shorter bouts. Fragmentation of the daily sleep-wake rhythm is associated with greater risk of incident AD and earlier cognitive decline in older humans. In spite of these correlative studies, whether or how chronic SF impacts the progression of AD has not been experimentally investigated. SF may be a better model of the sleep disruption associated with AD than the traditional approach of SR. Our studies of AD mouse models show that spontaneously occurring SF is associated with more severe Aβ accumulation and that experimentally-induced SF leads to Aβ accumulation and neuroinflammation. Besides SF, loss of SWS may exacerbate AD, and improving SWS may be beneficial in mild cognitive impairment (MCI) or even in AD. Since sleep disruption adversely affects the development of AD-related neuropathology, it is surprising that sleep enhancement (SE) strategies to consolidate sleep and increase SWS have not been adequately explored to slow or reverse these effects. Our overall working hypothesis is that a change in the quality of sleep, especially sleep fragmentation and loss of SWS, is more important than the quantity of sleep. Further, we hypothesize that the mechanism underlying these effects is primarily neuroinflammation, at least in part mediated by Aβ peptide deposition. We will use a unique, well-characterized mouse model, that exhibits AD-related Aβ pathology, neuroinflammation, and cognitive deficits. This project has three specific aims: (1) that SF will accelerate (and SE decelerate) AD progression; (2) that increases in Aβ accumulation mediates SF-induced neuroinflammation, neuropathology, and cognitive decline; and (3) that increases in neuroinflammation mediate SF-induced neuropathology and cognitive decline. We will use multiple novel approaches, including thermoneutral temperature manipulation, and a unique anti-inflammatory compound that has recently entered early stage clinical trials. Thus, these studies will elucidate the underlying mechanisms by which sleep disruption is linked to AD and will lay the groundwork for new therapeutic strategies.

慢性睡眠中断，由工作安排、噪音暴露、家庭责任、睡眠障碍或