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

阿尔茨海默病睡眠缺失神经损伤的细胞和分子基础

• 批准号: 10373983
• 负责人: NIRMALA NIRINJINI NAIDOO
• 金额: $ 73.12万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10373983
• 关键词: Abbreviations; Acute; Alzheimer' s Disease; Back; Behavioral; Biochemical; Brain region; CCAAT-Enhancer-Binding Proteins; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calmodulin; Calpain; Chronic; Developed Countries; Elderly; Endoplasmic Reticulum; Enzymes; Feeds; GRP78 gene; Gliosis; Hippocampus (Brain); Human; Impairment; Injury; Inositol; Mediating; Microinjections; Modeling; Modification; Molecular; Molecular Chaperones; Mus; Neurons; PRKR gene; Pathologic; Pharmacology; Phosphotransferases; Play; Rest; Risk Factors; Role; Sleep; Sleep Deprivation; Tauopathies; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; United States; Viral Vector; Wakefulness; activating transcription factor; effectiveness testing; endoplasmic reticulum stress; in vivo; in vivo calcium imaging; knock-down; mouse model; nerve injury; neurobehavioral; neuron loss; prevent; protein kinase R; response; tau Proteins; tau aggregation; tau mutation; tau phosphorylation; tau-1; therapeutic target

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.

抽象的 慢性短睡眠（CSS）在发达国家很常见，但很可能是影响睡眠质量的一个关键因素。 阿尔茨海默病 (AD)，老年人中最常见的 tau 蛋白病。睡眠不足会导致 tau 蛋白急剧升高 在人类和小鼠中，我们最近发现 CSS 加速了 P301S tau 蛋白病鼠模型中的 tau 蛋白病，增加了 tau 蛋白病的各个方面，包括可溶性 tau 寡聚体、病理性 tau 聚集、神经胶质增生、神经元丢失和神经行为障碍。事实 tau蛋白病的各个方面都受到睡眠不足的影响，这使我们推测CSS针对一个关键 上游引发因素。海马钙/钙调蛋白依赖性激酶 II (HC CAMKII) 神经元 是 AD 中最脆弱的神经元之一，并表现出早期 tau 积累。我们发现 CSS 大量增加 HC CAMKII 神经元中的钙瞬变，激活 CAMKII 和钙蛋白酶，并且 诱导未代偿的内质网应激并导致分子伴侣 BiP 丧失。我们的整体 假设 CSS 导致 HC CAMKII 神经元细胞内钙爆发过多，导致 持续的 CAMKII 和钙蛋白酶激活、致病性 tau 修饰和慢性失代偿 内质网应激伴随 BiP 的丧失，积极反馈以维持损伤。在这里我们 建议严格测试我们工作模型的每个组成部分在生化、病理学方面的作用 P301S 模型中 tau 蛋白病的行为方面和 Tau 蛋白病的 CSS 加速。在目标 1 中，我们 将测试 CSS 增加的 HC CAMKII 神经元中的钙和钙蛋白酶在 CSS HC tau 变化中的作用 通过基因抑制局部 HC CAMKII 钙和钙蛋白酶，同时验证抑制的钙 CAMKII 神经元的体内钙成像瞬态。在目标 2 中，使用药物抑制和 有条件的 HC 转基因敲低 CAMKII 跨 CSS，我们将确定 CAMKII 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 减少的 BiP 在 tau 蛋白病的时间进展中的作用以及 CSS 对 tau 蛋白病的影响。 总的来说，拟议的研究将确定CSS加速的重要体内机制 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蛋白病进展的一般情况。