Sleep Fragmentation and Alzheimer’s Disease

睡眠碎片化与阿尔茨海默病

• 批准号: 10611958
• 负责人: ADAM D BACHSTETTER
• 金额: $ 72.93万
• 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/10611958
• 关键词: Abeta clearance; Acceleration; 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; Deceleration; Dementia; Demographic Factors; Deposition; Development; Disease Progression; Exhibits; Family; Frequencies; Human; Impaired cognition; Impairment; Inflammation; Inflammatory; Knock-in Mouse; Life; Life Style; Light; Link; Mediating; Mediator; Medical History; Microglia; Modeling; Moods; Mus; Nerve Degeneration; Noise; Pathology; Personal Satisfaction; Pharmaceutical Preparations; 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; improvement on sleep; middle age; mild cognitive impairment; mouse model; neuroinflammation; neuropathology; neurotoxic; noise exposure; novel; novel strategies; novel therapeutic intervention; pharmacologic; 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.

由于工作时间表，噪音暴露，家庭义务，睡眠障碍或 生活方式的选择是当代生活的普遍特征。睡眠问题影响多达40％的AD患者， 可能会在认知障碍之前增加十多年，并且随着疾病的发展而更糟。也 影响情绪和福祉，睡眠中断可能会导致AD神经病理学的发展，例如 通过降低淀粉样β（Aβ）的清除率，并促进涉及的神经毒性促炎态 星形胶质细胞和小胶质细胞。睡眠中断可能包括减少总睡眠（睡眠限制[SR]），深度丧失 睡眠（也称为慢波睡眠[SWS]，以大放大器，低频电活动为特征）， 睡眠（SF）分裂成较短的回合。每日睡眠唤醒节奏的分裂是相关的 由于人类的出现风险更大，并且更早的认知下降。尽管有这些相关性 研究，慢性SF是否影响AD的进展尚未进行实验研究。 SF可能是与SR的传统方法相比，与AD相关的睡眠破坏的更好模型。我们的 AD小鼠模型的研究表明，赞助的SF与更严重的Aβ有关 积累和实验诱导的SF导致Aβ的积累和神经炎症。除了 SF，SWS的损失可能加剧广告，而改善SWS可能对轻度认知障碍有益 （MCI）甚至在广告中。由于睡眠中断会对广告相关的神经病理学的发展产生不利影响，因此 令人惊讶的是，增强睡眠（SE）巩固睡眠和增加SW的策略尚未 适当探索以减慢或逆转这些影响。我们的总体工作假设是改变 睡眠质量，尤其是睡眠碎片和SW的丧失，比睡眠数量更重要。 此外，我们假设这些作用的基础机制是主要的神经炎症，至少在 由Aβ肽沉积介导的部分。我们将使用展示的独特，良好的鼠标模型 广告相关的Aβ病理，神经炎症和认知缺陷。该项目具有三个特定的目标：（1） 该SF将加速（并减速）AD的进展； （2）增加Aβ加速度培养基 SF引起的神经炎症，神经病理学和认知能力下降； （3）增加 神经炎症介导SF诱导的神经病理学和认知能力下降。我们将使用多本小说 方法，包括热温度操纵，以及独特的抗炎化合物 最近进入了早期临床试验。这是这些研究将通过 哪些睡眠中断与AD有关，并将为新的治疗策略奠定基础。

项目成果

Space-occupying brain lesions, trauma-related tau astrogliopathy, and ARTAG: a report of two cases and a literature review.

• DOI: 10.1186/s40478-021-01152-3
• 发表时间: 2021-03-23
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Bachstetter AD;Garrett FG;Jicha GA;Nelson PT
• 通讯作者: Nelson PT

The localization of molecularly distinct microglia populations to Alzheimer's disease pathologies using QUIVER.

• DOI: 10.1186/s40478-023-01541-w
• 发表时间: 2023-03-18
• 期刊: ACTA NEUROPATHOLOGICA COMMUNICATIONS
• 影响因子: 7.1
• 作者: Shahidehpour, Ryan K.;Nelson, Abraham S.;Sanders, Lydia G.;Embry, Chloe R.;Nelson, Peter T.;Bachstetter, Adam D.
• 通讯作者: Bachstetter, Adam D.

The amyloid-β peptide: Guilty as charged?

淀粉样β肽：有罪吗？

• DOI: 10.1016/j.bbadis.2023.166945
• 发表时间: 2024
• 期刊: Biochimica et biophysica acta. Molecular basis of disease
• 作者: Murphy,MPaul;Buzinova,ValeriaA;Johnson,CarrieE
• 通讯作者: Johnson,CarrieE

Chronic Fragmentation of the Daily Sleep-Wake Rhythm Increases Amyloid-beta Levels and Neuroinflammation in the 3xTg-AD Mouse Model of Alzheimer's Disease.

• DOI: 10.1016/j.neuroscience.2021.11.042
• 发表时间: 2022-01-15
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Duncan MJ;Guerriero LE;Kohler K;Beechem LE;Gillis BD;Salisbury F;Wessel C;Wang J;Sunderam S;Bachstetter AD;O'Hara BF;Murphy MP
• 通讯作者: Murphy MP