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

摘要 散发性阿尔茨海默病(AD)症状出现时的年龄和时间进展可以 几十年来各不相同。早期的认知衰退会对个人和社会产生巨大的影响，但人们对此知之甚少 影响阿尔茨海默病发生和发展的机制。蓝斑(LC)神经元早期证据 Tau蛋白在AD中的沉积和早期变性，并可能有助于tau在脑内的扩散 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 神经细胞，导致线粒体过度乙酰化、氧化性神经损伤和变性。在预赛中 研究发现，淀粉样前体蛋白(APP)单基因敲入小鼠(APPki)的证据增强 对ISS诱导的线粒体超乙酰化和氧化应激的敏感性以及ISS产生的 LC神经元A1-42和tau的显著增加，LC神经元的显著变性和早期认知 减损。值得注意的是，在ISS术后两个月，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，早期生命中的代谢应激 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反应，进而促进 前馈神经元内代谢损伤，加速AD的发生和/或进展。要深入了解 ISS对LC损伤的相关性及其对AD进展的影响，我们建议实施新的小鼠 靶向病毒载体、Stop-loxP/cre小鼠和CRISPR/Cas9 loxP/cre小鼠模型以改变LC水平 Tau、线粒体sirtuin 3活性和A1-x。我们将检验以下假设：(1)ISS是 足够的代谢应激源使LC神经元持续积聚tau乙酰化 神经元和从LC神经元到细胞的tau传播病理性tau的传播被 (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能力 Tau，减轻ISS诱导的APPki小鼠的变性和延缓认知能力下降；以及(3)LC 神经元内A对ISS增加的LC tau乙酰化和蓄积、LC变性、皮质 ISS tau的繁殖和加速认知功能衰退的进程。这些研究将告知 青春期慢性睡眠缺失在AD进展中的意义及对LC的认识 阿尔茨海默病进展机制中神经元内A--tau蓄积与代谢稳态的相互作用 这反过来将揭示潜在治疗靶点的前景。

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.