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.

由于工作安排、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一个普遍特征，睡眠问题影响着高达 40% 的 AD 患者。 可能先于认知障碍十多年，并且随着疾病的进展而恶化。 影响情绪和健康，睡眠中断可能会导致 AD 神经病理学的发展，例如， 通过减少淀粉样蛋白-β (Aβ) 的清除并促进神经毒性促炎状态，包括 星形胶质细胞和小胶质细胞的睡眠中断可能包括总睡眠时间减少（睡眠限制 [SR]）、深度睡眠丧失。 睡眠（也称为慢波睡眠 [SWS]，以大幅度、低频电活动为特征）， 睡眠（SF）的碎片化与每日睡眠-觉醒节律的碎片化有关。 尽管存在这些相关性，但老年人患 AD 的风险更大，认知能力更早下降。 研究表明，慢性 SF 是否或如何影响 AD 的进展尚未得到实验研究。 与传统的 SR 方法相比，SF 可能是 AD 相关睡眠中断的更好模型。 AD 小鼠模型的研究表明，自发发生的 SF 与更严重的 Aβ 相关 此外，实验诱导的 SF 会导致 Aβ 积累和神经炎症。 SF、SWS 丧失可能会使 AD 恶化，而改善 SWS 可能有益于轻度认知障碍 (MCI) 甚至 AD 中，由于睡眠中断会对 AD 相关神经病理学的发展产生不利影响。 令人惊讶的是，巩固睡眠和增加 SWS 的睡眠增强 (SE) 策略尚未得到实施。 我们的总体工作假设是，要进行充分的探索来减缓或扭转这些影响。 睡眠质量，尤其是睡眠碎片化和SWS丧失，比睡眠数量更重要。 此外，我们发现这些影响的机制主要是神经炎症，至少在 我们将使用一个独特的、特征良好的小鼠模型，该模型表现出 Aβ 肽沉积介导的部分。 AD 相关的 Aβ 病理学、神经炎症和认知缺陷该项目有三个具体目标：(1) SF 将加速（和 SE 减缓）AD 进展 (2) 增加 Aβ 积累介导； SF 引起的神经炎症、神经病理学和认知能力下降；以及 (3) 神经炎症介导SF引起的神经病理学和认知能力下降我们将使用多本小说。 方法，包括热中性温度控制和独特的抗炎化合物 最近已进入早期临床试验，因此，这些研究将通过以下方式阐明其潜在机制。 睡眠障碍与 AD 相关，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