Cellular and Molecular Basis of Sleep Loss Neural Injury in Alzheimer Disease

摘要 慢性短睡眠（CSS）在发达国家很常见，但可能是一个关键的修改器， 阿尔茨海默病（AD）是老年人中最常见的tau蛋白病。睡眠不足会急剧增加tau蛋白 在人类和小鼠中，我们最近发现CSS加速了 在P301 S tau蛋白病鼠模型中，增加了tau蛋白病的所有方面，包括可溶性 tau寡聚体、病理性tau聚集、神经胶质增生、神经元损失和神经行为损伤。的事实 tau蛋白病的各个方面都受到睡眠不足的影响，这让我们假设CSS针对的是一个关键点， 上游启动因子海马钙/钙调蛋白依赖性激酶II（HC CAMK II）神经元 是AD中最脆弱的神经元之一，并显示早期tau积累。我们发现 CSS大量增加HC CAMK II神经元中的钙瞬变，激活CAMK II和钙蛋白酶， 诱导失代偿性内质网应激，分子伴侣BiP缺失。我们的整体 一种假设是CSS导致HC CAMK II神经元中过量的细胞内钙爆发， 持续的CAMKII和钙蛋白酶激活，致病性tau蛋白修饰，以及慢性失代偿 内质网应激伴随BiP的损失，其正反馈以使损伤永久化。这里我们 建议严格测试我们的工作模型的每个组成部分在生物化学，病理学， 和tau蛋白病的行为方面以及P301 S模型中tau蛋白病的CSS加速。目标1： 将测试CSS增加的钙和钙蛋白酶在CSS HC tau变化中在HC CAMK II神经元中的作用 通过遗传抑制局部HC CAMKII钙和钙蛋白酶，同时验证抑制的钙 瞬时与CAMK II神经元的体内钙成像。在目标2中，使用药理学抑制和 条件性HC转基因敲除CAMKII跨CSS，我们将确定CAMKII在其中的作用 诱导CSS诱导的HC ER应激和CSS对tau蛋白病的影响，在目标3中，我们将严格测试 CSS还原的BiP在tau蛋白病的时间进展中的作用和CSS对tau蛋白病的影响。 总的来说，拟议的研究将确定重要的体内机制，CSS加速 tau蛋白病的时间进展，并将证实减轻CSS恶化的治疗途径 tau蛋白病和tau蛋白病的进展。

ABSTRACT Chronic short sleep (CSS) is common in developed countries and yet is likely to be a key modifier of Alzheimer disease (AD), the most prevalent tauopathy in older adults. Sleep loss acutely increases tau in humans and in mice, and we have recently shown that CSS hastens the temporal progression of tauopathy in the P301S murine model of tauopathy, increasing all aspects of tauopathy, including soluble tau oligomers, pathologic tau aggregation, gliosis, neuron loss and neurobehavioral impairment. The fact that all aspects of tauopathy are impacted by sleep loss leads us to hypothesize that CSS targets a key upstream initiating factor. Hippocampal calcium/calmodulin dependent kinase II (HC CAMKII) neurons are among some of the most vulnerable neurons in AD and show early tau accumulation. We find that CSS massively increases calcium transients in HC CAMKII neurons, activates CAMKII and calpain, and induces uncompensated endoplasmic reticulum stress with loss of molecular chaperone BiP. Our overall hypothesis is that CSS results in excessive intracellular calcium bursts in HC CAMKII neurons, leading to sustained CAMKII and calpain activation, pathogenic tau modifications, and chronic uncompensated endoplasmic reticulum stress with loss of BiP that feeds back positively to perpetuate injury. Here we propose to critically test the role of each component of our working model in the biochemical, pathological and behavioral aspects of tauopathy and CSS-hastening of tauopathy in the P301S model. In Aim 1, we will test the role of CSS-increased calcium and calpain in HC CAMKII neurons in the CSS HC tau changes by genetically suppressing local HC CAMKII calcium and calpain, while verifying suppressed calcium transients with in vivo calcium imaging of CAMKII neurons. In Aim 2, using pharmacologic inhibition and conditional HC transgenic knock down of CAMKII across CSS, we will determine to what role CAMKII induces CSS-induced HC ER stress and CSS effects on tauopathy, and in Aim 3, we will critically test the role of CSS-reduced BiP in the temporal progression of tauopathy and CSS effects on tauopathy. Collectively, the proposed studies will identify important in vivo mechanisms by which CSS hastens the temporal progression of tauopathy and will substantiate therapeutic avenues to lessen CSS exacerbation of tauopathy and tauopathy progression in general.