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：
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
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/10640879
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 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

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.

项目概要选择性神经变性是阿尔茨海默病 (AD) 的一个关键致病因素，但其机制却不尽相同。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，但存在区域易感性。海马和内嗅皮层中与 AD 相关的神经变性，甚至在脆弱的神经元内也是如此。然而，随着最新技术的发展，一些细胞会提前消失，而另一些细胞则表现出更强的恢复能力。随着单细胞分析的改进，我们第一次能够检查驱动区域的变异性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)，它会增加疾病发生率在中枢神经系统内，apoE 主要产生于携带者。星形胶质细胞以及神经元中的 apoE4 表达在应激、损伤和衰老后都会减少。突触可塑性，损害突触发生，并降低体外和体内的突触密度。该提议基于 (1) 我们的单核 RNA 测序数据。实验室揭示了神经元 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。定位于突触后密度，在那里它们限制长期增强，增强长期抑制，并在发育过程中以及潜在的神经退行性疾病中介导突触修剪。神经元 apoE 上调 MHC-I 的发现提供了对这两种蛋白的机制的深入了解 (2) 在 AD 患者中，神经元 apoE 表达与神经元 MHC-I 表达相关，进而预测 (3) 在 AD 模型小鼠或培养的原代神经元中，神经元特异性 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。为了利用这些新发现和单细胞分析的最新技术改进，该提案旨在确定 apoE 高表达和 MHC-I 高表达神经元群体并探索它们 apoE-AD易感脑区和AD抵抗脑区的选择性神经变性关系不同年龄具有不同 apoE 基因型的 KI 小鼠（目标 1）我们还将确定 apoE 如何调节。 MHC-I 的神经表达以及该表达如何导致阿尔茨海默病相关病理（Aim 2).最后，我们建议确定引起apoE和MHC-I介导的神经元损失的程度通过向小胶质细胞发出信号（目标 3），该信号与阿尔茨海默病的发病机制密切相关。拟议研究的结果应阐明区域性、细胞类型特异性、以及细胞内类型对阿尔茨海默病的选择性脆弱性。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neuronal apoE4 induces early hyperexcitability in select populations of hippocampal neurons by altering Nell2 expression.

神经元 apoE4 通过改变 Nell2 表达来诱导选定的海马神经元群体的早期过度兴奋。

DOI：
发表时间：
2023-08-29
期刊：
影响因子：
0
作者：
Jang, Sung;Tabuena, Dennis R;Grone, Brian;Yip, Oscar;Blumenfeld, Jessica;Koutsodendris, Nicole;Ding, Leonardo;Xu, Qin;Yoon, Seo Yeon;Huang, Yadong;Zilberter, Misha
通讯作者：
Zilberter, Misha