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

基本信息

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
项目类别：
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&apos 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

项目摘要

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，但很可能是阿尔茨海默氏病（AD），是老年人最普遍的tauopathy。睡眠丧失急性增加tau 在人类和小鼠中，我们最近表明CSS加快了时间的进步 p3auopathy的P301s鼠模型中的tauopathy，增加了tauopathy的所有方面，包括可溶性 tau低聚物，病理学tau聚集，神经胶质病，神经元丧失和神经行为障碍。事实 tauopathy的所有方面都受到睡眠损失的影响，使我们假设CSS针对关键上游启动因子。海马钙/钙调蛋白依赖激酶II（HC CAMKII）神经元是AD中最脆弱的神经元中的一些，并显示早期Tau的积累。我们发现 CSS大量增加了HC CAMKII神经元中的钙瞬变，激活Camkii和Calpain，并且诱导无补偿的内质网应激，并导致分子伴侣BIP的损失。我们的整体假设是CSS导致HC CaMKII神经元中过度细胞内钙爆发，领先为了持续CAMKII和钙蛋白酶激活，致病性TAU修饰和慢性无偿内质网应激，损失BIP，其积极地反馈以使损伤永存。我们在这里提议批判性地测试我们工作模型的每个组成部分在生化，病理学中的作用在P301S模型中，Tauopathy和Tauopathy的CSS危机的行为方面。在AIM 1中，我们将测试CSS钙和钙蛋白酶在CSS HC TAU中的HC CAMKII神经元中的作用通过遗传抑制局部HC Camkii钙和钙蛋白酶，同时验证抑制钙带有CAMKII神经元体内钙成像的瞬变。在AIM 2中，使用药理抑制和有条件的HC转基因在CSS上击倒Camkii，我们将确定CAMKII的作用诱导CSS诱导的HC ER应力和CSS对Tauopathy的影响，在AIM 3中，我们将进行严格的测试 CSS还原BIP在tauopathy和CSS对tauopathy的影响中的作用。总的来说，拟议的研究将确定CSS加速的重要体内机制 tauopathy的时间进展，并将证实治疗途径以减轻CSS加剧一般来说，陶氏病和陶氏病的进展。