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: 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
• 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' 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; 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

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 选择性神经退行性变是阿尔茨海默病（AD）的一个重要致病因素;然而， 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。有区域性的易感性， AD相关的海马和内嗅皮质神经变性。即使在脆弱的神经元内 然而，在种群中，一些细胞很早就失去了，而另一些细胞则证明更具弹性。最近的技术 单细胞分析的改进，我们能够第一次检查驱动区域性的变异性， 和细胞对神经变性的易感性的差异。 阿尔茨海默病的主要遗传风险因素是载脂蛋白E4（apoE 4），它增加了疾病的发生率。 风险和降低发病年龄的载体。在中枢神经系统内，apoE主要在 星形胶质细胞，而且在应激、损伤和老化后的神经元中也是如此。神经元apoE 4表达减少 突触可塑性，损害突触发生，并降低体外和体内的突触密度。 这一建议是基于有趣的初步研究。(1)来自我们的单核RNA测序数据 实验室已经揭示了神经元apoE和主要组织相容性复合物的神经元表达之间的联系 I类（MHC-I）。与apoE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 局限于突触后密度，在那里它们限制长时程增强，增强长时程抑制， 并在发育过程中以及潜在地在神经退行性疾病中介导突触修剪。我们 神经元apoE上调MHC-I的发现提供了对这两种蛋白质 潜在地协同作用，导致突触丧失并最终导致选择性神经变性。(2)在 在AD患者中，神经元apoE表达与神经元MHC-I表达相关，这反过来预测了AD患者的神经元apoE表达与神经元MHC-I表达相关， Tau病理的严重程度。(3)在AD模型小鼠或培养的原代神经元中， 降低神经元MHC-I表达，挽救神经元和突触损失，建立因果关系。 AD中神经元apoE、MHC-I上调和选择性神经变性之间的关系 为了利用这些新的发现和单细胞分析的最新技术改进， 目的是确定apoE高表达和MHC-I高表达的神经元群体，并探索它们的作用。 与AD易感和AD抵抗脑区apoE选择性神经变性的关系 在不同年龄具有不同apoE基因型的KI小鼠（目的1）。我们还将确定apoE是如何调节 MHC-I的神经元表达以及这种表达如何导致阿尔茨海默病相关的病理（Aim 2）。最后，我们建议确定这种apoE和MHC-I介导的神经元损失的程度 通过向小胶质细胞（Aim 3）发出信号，这与阿尔茨海默病的发病机制密切相关。的 拟议研究的结果应阐明区域性，细胞类型特异性， 和细胞内类型选择性易患阿尔茨海默病。