Neuronal ApoE Drives Selective Neurodegeneration in Alzheimer's Disease

神经元 ApoE 驱动阿尔茨海默病的选择性神经变性

基本信息

批准号：
10458692
负责人：
YADONG HUANG
金额：
$ 81.73万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10458692
关键词：
Ablation Age Age of Onset Aging Alzheimer associated neurodegeneration Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Apolipoprotein E Astrocytes Biological Models Brain region CRISPR/Cas technology Cell Nucleus Cells Cerebellum Clustered Regularly Interspaced Short Palindromic Repeats Data Data Set Development Disease Resistance Genes Genotype Goals Hippocampus (Brain)Human Immune response Impairment In Vitro Individual Induced pluripotent stem cell derived neurons Injury Knock-in Knock-in Mouse Knock-out Late Onset Alzheimer Disease Lead Light Link Long-Term Depression Long-Term Potentiation Longevity Major Histocompatibility Complex Mediating Microglia Molecular Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Outcome Pathogenesis Pathology Pathway interactions Patients Population Predisposition Protein Isoforms Proteins Regulation Research Role Severities Signal Transduction Small Nuclear RNA Stress Synapses Synaptic plasticity Technology Time Transgenic Mice Translating Up-Regulation Work age related aged apolipoprotein E-3 apolipoprotein E-4 base cell type density disorder risk entorhinal cortex genetic risk factor in vivo induced pluripotent stem cell insight mild cognitive impairment mouse model neuron loss novel prevent single cell analysis single-cell RNA sequencing synaptic pruning synaptogenesis tau Proteins tool transcriptome sequencing

项目摘要

PROJECT SUMMARY Selective neurodegeneration is a critical causal factor in Alzheimer’s disease (AD); however, the mechanisms that lead some neurons to perish while others remain resilient are unknown. There is regional susceptibility to AD-related neurodegeneration in the hippocampus and entorhinal cortex. Even within vulnerable neuronal populations, however, some cells are lost early while others prove more resilient. With recent technical improvements in single-cell analysis, we are able for the first time to examine the variability that drives regional and cellular differences in susceptibility to neurodegeneration. The major genetic risk factor for Alzheimer’s disease is apolipoprotein E4 (apoE4), which increases disease risk and decreases age of onset in carriers. Within the central nervous system, apoE is produced primarily in astrocytes but also in neurons following stress, injury, and aging. Neuronal apoE4 expression diminishes synaptic plasticity, impairs synaptogenesis, and decreases synaptic density both in vitro and in vivo. This proposal is based on intriguing preliminary studies. (1) Single-nucleus RNA-sequencing data from our lab have revealed a link between neuronal apoE and neuronal expression of the major histocompatibility complex class I (MHC-I). Like apoE, MHC-I is expressed in neurons following stress, injury, and aging. Neuronal MHC-I is localized to post-synaptic densities, where they limit long-term potentiation, enhance long term depression, and mediate synaptic pruning during development and, potentially, in neurodegenerative diseases. Our discovery of neuronal apoE upregulation of MHC-I provides insight into the mechanism by which both proteins potentially work in concert to contribute to synapse loss and eventually to selective neurodegeneration. (2) In AD patients, neuronal apoE expression correlates with neuronal MHC-I expression, which in turn predicts severity of Tau pathologies. (3) In AD model mice or cultured primary neurons, neuron-specific apoE4 knock-out decreases neuronal MHC-I expression and rescues neuronal and synaptic loss, establishing a causal relationship between neuronal apoE, upregulation of MHC-I, and selective neurodegeneration in AD. To capitalize on these novel findings and recent technical improvements in single-cell analyses, this proposal aims to determine the apoE-expression-high and MHC-I-expression-high neuron populations and explore their relationships with selective neurodegeneration across AD-susceptible and AD-resistant brain regions of apoE- KI mice with different apoE genotypes at different ages (Aim 1). We will also determine how apoE is regulating neuronal expression of MHC-I and how this expression leads to Alzheimer’s disease-related pathologies (Aim 2). Finally, we propose to determine the extent to which this apoE and MHC-I-mediated neuronal loss is caused by signaling to microglia (Aim 3), which has been heavily implicated in Alzheimer’s disease pathogenesis. The outcome of the proposed studies should shed light on the mechanisms underlying regional, cell-type-specific, and within-cell-type selective vulnerability to Alzheimer’s disease.

项目摘要选择性神经变性是阿尔茨海默氏病（AD）的关键因果因素；但是，机制这导致一些神经元灭亡，而另一些神经元尚不清楚。有区域易感性海马和内嗅皮层中与广告相关的神经变性。即使在脆弱的神经元内但是，种群有些细胞丢失了，而另一些细胞则证明更有弹性。与最近的技术单细胞分析的改进，我们首次能够检查驱动区域的可变性和细胞对神经变性的敏感性的差异。阿尔茨海默氏病的主要遗传危险因素是载脂蛋白E4（APOE4），它增加了疾病风险并降低载体的发病年龄。在中枢神经系统中，APOE在主要中产生压力，损伤和衰老后的星形胶质细胞，但在神经元中也是如此。神经元APOE4表达减少突触可塑性，会损害突触发生，并在体外和体内降低突触密度。该建议基于有趣的初步研究。（1）来自我们实验室揭示了主要组织相容性复合物的神经元APOE与神经元表达之间的联系 I类（MHC-I）。像APOE一样，MHC-I在压力，损伤和衰老后在神经元中表达。神经元MHC-I 被局部为突触后密度，它们限制了长期增强，增强了长期抑郁症，并在发育过程中介导突触修剪，并可能在神经退行性疾病中进行介导。我们的 MHC-I的神经元APOE上调的发现提供了对两种蛋白质的机制的见解有可能协同工作有助于突触丧失，并最终导致选择性神经变性。（2）英寸 AD患者，神经元APOE表达与神经元MHC-I表达相关，这反过来预测 tau病理的严重程度。（3）在AD模型小鼠或培养的原发性神经元中，神经特异性APOE4敲除降低神经元MHC-I表达并挽救神经元和突触损失，建立催化 AD中的神经元APOE，MHC-I上调和选择性神经变性之间的关系。为了利用这些新颖的发现和单细胞分析的最新技术改进，该建议旨在确定APOE-Expression-High和MHC-I-E表达高神经元种群并探索他们 apoE的广告敏感和抗ad的大脑区域的选择性神经变性的关系 - 具有不同年龄的不同APOE基因型的Ki小鼠（AIM 1）。我们还将确定APOE如何调节 MHC-I的神经元表达以及该表达如何导致阿尔茨海默氏病与疾病相关的病理（AIM 2）。最后，我们建议确定该APOE和MHC-I介导的神经元丧失的程度通过向小胶质细胞发出信号（AIM 3），这与阿尔茨海默氏病发病机理有关。这拟议的研究的结果应阐明区域，细胞类型的机制，以及对阿尔茨海默氏病的选择性选择性脆弱性。