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

摘要 阿尔茨海默病的发病年龄和散发性阿尔茨海默病（AD）的时间进展可以 几十年来变化。早期认知能力下降会对个人和社会产生巨大影响，但人们对此知之甚少。 影响AD发病和进展的机制。蓝斑（LC）神经元的证据早期 AD中tau蛋白沉积和早期变性，可能有助于tau蛋白在AD中的扩散。 前脑间歇性短睡眠（ISS），在现代社会中很常见，扰乱了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 研究发现，淀粉样前体蛋白（APP）单基因敲入小鼠（APPki）的证据表明， 对ISS诱导的线粒体高乙酰化和氧化应激的易感性，ISS产生一种 LC神经元A β 1-42和tau的急剧增加，LC神经元明显变性，认知能力早期 损伤值得注意的是，ISS后两个月，LC神经元tau乙酰化和A β 1-42保持升高， 空间物体识别受损。我们工作的总体假设是， 特定的神经元群激活受影响的神经元内的淀粉样蛋白和tau蛋白反应，这反过来又促进 前馈神经元内代谢损伤加速AD发作和/或进展。为了深入了解 ISS导致的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小鼠的模型，以改变LC水平。 tau、线粒体sirtuin 3活性和A β 1-x。我们将测试以下假设：（1）ISS是 足够的LC神经元代谢应激物，导致LC中持续的tau乙酰化积累 神经元，并且从LC神经元的tau传播与病理性tau的细胞到细胞的传播通过以下方式被改变： ISS;（2）改善线粒体脱乙酰酶活性可改善LC神经元对毒性淀粉样蛋白的清除， tau，减轻ISS诱导的变性并延迟APPki小鼠的认知下降;和（3）LC 神经元内A β对于ISS增加的LC tau乙酰化和积累、LC变性、皮质 ISS tau蛋白传播并加速认知衰退的进展。这些研究将为 青年期慢性睡眠丧失在AD进展中意义及对LC的认识 AD进展机制中神经元内A β tau蓄积和代谢稳态相互作用 这反过来将揭示潜在的治疗靶点的前景。

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.