Short Sleep: Locus Coeruleus Metabolics and the Temporal Progression of Alzheimers

短睡眠：蓝斑代谢和阿尔茨海默病的时间进展

• 批准号: 9195434
• 负责人: SIGRID C VEASEY
• 金额: $ 313.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195434
• 关键词: Acetylation; Acetyltransferase; Address; Affect; Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Autophagocytosis; CRISPR/Cas technology; Cells; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive deficits; Deacetylase; Deposition; Disease; Disease Progression; Dopamine; Figs - dietary; Homeostasis; Impaired cognition; Injury; Knock-in Mouse; Left; Life; Mediating; Metabolic; Metabolic stress; Mitochondria; Mixed Function Oxygenases; Modeling; Modification; Molecular; Molecular Models; Mus; Mutation; Nerve Degeneration; Neurites; Neuronal Injury; Neurons; Onset of illness; Oxidative Stress; Post-Translational Protein Processing; Predisposition; Prosencephalon; Research Design; Rest; Role; Sleep; Societies; Source; Stress; Testing; Time; Up-Regulation; Viral Vector; Wakefulness; Wild Type Mouse; Work; age effect; cognitive function; cognitive performance; feeding; improved; injured; insight; locus ceruleus structure; molecular modeling; mouse model; nerve injury; neuronal cell body; neuropathology; noradrenergic; novel; novel therapeutics; object recognition; prevent; recombinase; response; stressor; symptomatology; tau Proteins; tau aggregation; therapeutic target; vector; young adult

ABSTRACT The age at onset of symptomatology and the temporal progression of sporadic Alzheimer's disease (AD) can vary by decades. Earlier cognitive decline carries tremendous personal and societal impact, yet little is known of mechanisms influencing the onset and progression of AD. Locus coeruleus (LC) neurons evidence early deposition of tau protein and early degeneration in AD and may contribute to the spreading of tau within the forebrain. Intermittent short sleep (ISS), common in modern societies, disturbs metabolic homeostasis in LC neurons, resulting in mitochondrial hyperacetylation, oxidative neural injury and degeneration. In Preliminary Studies, we find that the amyloid precursor protein (APP) single knock-in mouse (APPki) evidences heightened susceptibility to ISS-induced mitochondrial hyperacetylation and oxidative stress and that ISS produces a robust increase in LC neuronal A1-42 and tau, marked degeneration of LC neurons and earlier cognitive impairment. Remarkably, two months after ISS, LC neuronal tau acetylation and A1-42 remain elevated, and spatial object recognition is impaired. The overall hypothesis for our work is that early life metabolic stress in specific groups of neurons activates amyloid and tau responses within affected neurons that, in turn, promote feed forward intraneuronal metabolic injury that hastens AD onset and/or progression. To gain insight into the relevance of LC injury from ISS and its influence on AD progression, we propose to implement novel murine models of targeted viral vectors, STOP-LoxP/cre mice and CRISPR/Cas9 LoxP/cre mice to modify LC levels of tau, mitochondrial sirtuin 3 activity, and A1-x, respectively. We will test the following hypotheses: (1) that ISS is sufficient a metabolic stressor for LC neurons to result in a sustained tau acetylation accumulation in LC neurons and that tau propagation from LC neurons with cell to cell spread of pathological tau is modified by ISS; (2) that improving mitochondrial deacetylase activity improves LC neuron clearance of toxic amyloid and tau, lessens ISS-induced degeneration and delays cognitive decline in the APPki mouse; and (3) that LC intraneuronal A is essential for ISS-increased LC tau acetylation and accumulation, LC degeneration, cortical ISS tau propagation and hastening the progression of cognitive decline. These studies will inform the significance of young adulthood chronic sleep loss in AD progression and advance our understanding of LC intraneuronal A tau accumulation and metabolic homeostasis interactions in mechanisms of AD progression that in turn will unveil the promise of potential therapeutic targets.

抽象的 散发性阿尔茨海默病 (AD) 症状出现的年龄和时间进展可以 相差数十年。早期认知能力下降会带来巨大的个人和社会影响，但人们知之甚少 影响 AD 发生和进展的机制。蓝斑 (LC) 神经元早期证据 AD 中 tau 蛋白的沉积和早期变性，可能有助于 tau 在 AD 中的扩散 前脑。现代社会中常见的间歇性短睡眠 (ISS) 会扰乱 LC 的代谢稳态 神经元，导致线粒体过度乙酰化、氧化性神经损伤和变性。初步阶段 研究发现，淀粉样前体蛋白（APP）单敲入小鼠（APPki）证据增强 对 ISS 诱导的线粒体过度乙酰化和氧化应激的易感性，并且 ISS 产生 LC 神经元 A1-42 和 tau 急剧增加，LC 神经元显着变性和早期认知 损害。值得注意的是，ISS 两个月后，LC 神经元 tau 乙酰化和 A1-42 仍然升高，并且 空间物体识别能力受损。我们工作的总体假设是，生命早期的代谢压力 特定的神经元群会激活受影响神经元内的淀粉样蛋白和 tau 蛋白反应，进而促进 前馈神经元内代谢损伤，加速 AD 的发作和/或进展。为了深入了解 ISS 造成的 LC 损伤的相关性及其对 AD 进展的影响，我们建议实施新型小鼠 靶向病毒载体模型、STOP-LoxP/cre 小鼠和 CRISPR/Cas9 LoxP/cre 小鼠模型可改变 LC 水平 分别为 tau、线粒体 Sirtuin 3 活性和 A1-x。我们将检验以下假设：（1）国际空间站是 为 LC 神经元提供足够的代谢应激源，导致 LC 中 tau 乙酰化持续积累 神经元和 LC 神经元的 tau 传播以及病理性 tau 的细胞间传播被修改 国际空间站； (2)提高线粒体脱乙酰酶活性可提高LC神经元对有毒淀粉样蛋白的清除率，并且 tau，减轻 ISS 诱导的退化并延缓 APPki 小鼠的认知衰退； (3) 信用证 神经元内 A 对于 ISS 增加的 LC tau 乙酰化和积累、LC 变性、皮质 ISS tau 传播并加速认知能力下降的进程。这些研究将告知 成年早期慢性睡眠不足在 AD 进展中的重要性并促进我们对 LC 的理解 AD进展机制中神经元内A tau蛋白积累和代谢稳态相互作用 这反过来又将揭示潜在治疗靶点的前景。