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

• 批准号: 10640879
• 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
• 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/10640879
• 关键词: Ablation; Age; Age of Onset; Aging; Alzheimer associated neurodegeneration; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Apolipoprotein E; Astrocytes; Biological Models; Brain region; CRISPR/Cas technology; Cells; Central Nervous System; Cerebellum; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Data Set; Development; Disease Resistance; Disease susceptibility; Genes; Genotype; Goals; Hippocampus; Human; Immune response; Impairment; In Vitro; Individual; Induced pluripotent stem cell derived neurons; Injury; Knock-in Mouse; Knock-out; Late Onset Alzheimer Disease; Lead; Link; Long-Term Depression; Long-Term Potentiation; Longevity; Major Histocompatibility Complex; Mediating; Microglia; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Population; Predisposition; Protein Isoforms; Proteins; Regulation; Research; Role; Severities; Signal Transduction; Stress; Synapses; Synaptic plasticity; Technology; Time; Transgenic Mice; Translating; Up-Regulation; Work; age related; aged; apolipoprotein E-3; apolipoprotein E-4; cell type; cohort; density; disorder risk; entorhinal cortex; genetic risk factor; improved; in vivo; induced pluripotent stem cell; insight; mild cognitive impairment; mouse model; neuron loss; novel; postsynaptic; prevent; resilience; single cell analysis; single nucleus RNA-sequencing; single-cell RNA sequencing; synaptic pruning; synaptogenesis; tau Proteins; tool

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.

项目总结 选择性神经变性是阿尔茨海默病(AD)的关键致病因素；然而，其机制 导致一些神经元死亡而另一些神经元保持弹性的原因尚不清楚。有地区性的易感性 海马区和内嗅区皮质中与AD相关的神经变性。即使在脆弱的神经元中 然而，群体中的一些细胞很早就消失了，而另一些细胞则被证明更具弹性。使用最近的技术 在单细胞分析方面的改进，我们第一次能够检查驱动区域 以及神经退行性变易感性的细胞差异。 阿尔茨海默病的主要遗传风险因素是载脂蛋白E4(ApoE4)，它会增加疾病 降低携带者的发病风险和发病年龄。在中枢神经系统内，载脂蛋白E主要是在 星形胶质细胞也存在于应激、损伤和衰老后的神经元中。神经元apoE4表达减弱 在体外和体内，突触可塑性，损害突触发生，并降低突触密度。 这项建议是基于耐人寻味的初步研究。(1)来自我们的单核RNA测序数据 实验室已经发现神经元载脂蛋白E和主要组织相容性复合体的神经元表达之间的联系 第I类(MHC-I)。像载脂蛋白E一样，MHC-I在应激、损伤和衰老后的神经元中表达。神经元MHC-I 定位于突触后的密度，在那里它们限制了长时增强，增强了长时抑制， 并在发育过程中调节突触修剪，可能在神经退行性疾病中也是如此。我们的 神经元载脂蛋白E上调MHC-I的发现为深入了解这两种蛋白的作用机制提供了线索 可能协同作用导致突触丢失，最终导致选择性神经变性。(2)在 AD患者神经元apoE表达与神经元MHC-I表达相关，进而预测 Tau病变的严重程度。(3)在AD模型小鼠或培养的原代神经元中，神经元特异性apoE4基因敲除 减少神经元MHC-I的表达，挽救神经元和突触的丢失，确定原因 神经元载脂蛋白E、MHC-I上调与AD选择性神经退行性变的关系 为了利用这些新发现和最近在单细胞分析方面的技术改进，这项提议 目的确定apoE高表达和MHC-I高表达神经元群体，并探讨其 载脂蛋白E易感和抗AD脑区选择性神经退行性变的关系 不同年龄、不同载脂蛋白E基因型的KI小鼠(目标1)。我们还将确定apoE是如何调节的 MHC-I的神经元表达及其如何导致阿尔茨海默病相关的病理(AIM 2)。最后，我们建议确定apoE和MHC-I介导的神经元丢失的程度 通过向小胶质细胞发出信号(AIM 3)，这与阿尔茨海默病的发病机制密切相关。这个 拟议研究的结果应有助于阐明区域、特定细胞类型、 以及细胞内类型对阿尔茨海默病的选择性易感性。