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: 10586062
• 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/10586062
• 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; Human; Impairment; Injury; Inositol; Mediating; Microinjections; Modeling; Modification; Molecular; Molecular Chaperones; Mus; Neurons; PRKR gene; Pathologic; Peptide Initiation Factors; Phosphotransferases; Play; Predisposition; 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; pharmacologic; prevent; protein kinase R; response; tau Proteins; tau aggregation; tau mutation; 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.

摘要 慢性短睡眠(CSS)在发达国家很常见，但很可能是 阿尔茨海默病(AD)，老年人中最常见的肌萎缩症。睡眠不足会显著增加tau 在人类和小鼠身上，我们最近表明，css加速了 顺势疗法在P301S小鼠模型中的顺势疗法，增加了顺势疗法的方方面面，包括可溶性 Tau寡聚体、病理性tau聚集、胶质细胞增厚、神经元丢失和神经行为障碍。事实是 紧张症的所有方面都会受到睡眠不足的影响，这让我们假设CS针对的是一个关键的 上游启动因素。海马钙/钙调蛋白依赖性激酶II(HC CaMKII)神经元 是阿尔茨海默病中最脆弱的神经元之一，并显示出早期tau的积累。我们发现 CS显著增加了HC CaMKII神经元的钙瞬变，激活了CaMKII和钙蛋白酶，并 诱导失代偿的内质网应激，分子伴侣Bip的丢失。我们的整体 假设是CS导致HC CaMKII神经元细胞内过度钙爆发，导致 持续的CaMKII和Calain激活，致病性tau修饰，以及慢性失代偿 内质网应激与BiP的丢失正反馈使损伤永久化。在这里我们 建议批判性地测试我们工作模型中每个组件在生化、病理 以及在P301S模型中伸展疗法的行为方面和伸展疗法的加速效应。在目标1中，我们 将测试css增加的钙和钙蛋白对HC CaMKII神经元在css中HC tau变化的作用 通过遗传抑制局部HC CaMKII钙和钙蛋白，同时验证被抑制的钙 CaMKII神经元的体内钙成像的瞬变。在目标2中，使用药物抑制和 有条件的HC转基因在整个CS中击倒CaMKII，我们将确定CaMKII扮演什么角色 诱导css诱导的HC ER应激和css对紧张症的影响，在目标3中，我们将严格测试 Css减少的Bip在直立性肌病的时间进展中的作用以及css对直立性肌病的影响。 总而言之，拟议的研究将确定重要的体内机制，通过这些机制，CSS加速了 肌萎缩侧索硬化症的时间进展，并将证实减轻CS恶化的治疗途径 直立性和直立性进展的一般情况。