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:
- 金额:$ 81.73万
- 依托单位:
- 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:
- 关键词:AblationAgeAge of OnsetAgingAlzheimer associated neurodegenerationAlzheimer disease preventionAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskApolipoprotein EAstrocytesBiological ModelsBrain regionCRISPR/Cas technologyCell NucleusCellsCerebellumClustered Regularly Interspaced Short Palindromic RepeatsDataData SetDevelopmentDisease ResistanceGenesGenotypeGoalsHippocampus (Brain)HumanImmune responseImpairmentIn VitroIndividualInduced pluripotent stem cell derived neuronsInjuryKnock-inKnock-in MouseKnock-outLate Onset Alzheimer DiseaseLeadLightLinkLong-Term DepressionLong-Term PotentiationLongevityMajor Histocompatibility ComplexMediatingMicrogliaMolecularNerve DegenerationNeuraxisNeurodegenerative DisordersNeuronsOutcomePathogenesisPathologyPathway interactionsPatientsPopulationPredispositionProtein IsoformsProteinsRegulationResearchRoleSeveritiesSignal TransductionSmall Nuclear RNAStressSynapsesSynaptic plasticityTechnologyTimeTransgenic MiceTranslatingUp-RegulationWorkage relatedagedapolipoprotein E-3apolipoprotein E-4basecell typedensitydisorder riskentorhinal cortexgenetic risk factorin vivoinduced pluripotent stem cellinsightmild cognitive impairmentmouse modelneuron lossnovelpreventsingle cell analysissingle-cell RNA sequencingsynaptic pruningsynaptogenesistau Proteinstooltranscriptome 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.
项目概要
选择性神经变性是阿尔茨海默病 (AD) 的关键致病因素;然而,这些机制
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。存在地区易感性
海马和内嗅皮层与 AD 相关的神经变性。即使在脆弱的神经元内
然而,在群体中,一些细胞很早就丢失了,而另一些细胞则表现出更强的恢复能力。凭借最近的技术
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
风险并降低携带者的发病年龄。在中枢神经系统中,apoE 主要产生于
星形胶质细胞也存在于压力、损伤和衰老后的神经元中。神经元apoE4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。
该提议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 在压力、损伤和衰老后的神经元中表达。神经元MHC-I
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。我们的
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
可能协同作用导致突触损失并最终导致选择性神经变性。 (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
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,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 与 AD 易感和 AD 抵抗脑区选择性神经变性的关系
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 的神经元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,我们建议确定造成 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。这
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(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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{{ truncateString('YADONG HUANG', 18)}}的其他基金
Develop AD Connectivity Maps with Human iPSC-Derived Brain Cells and their Use
使用人类 iPSC 衍生脑细胞开发 AD 连接图及其用途
- 批准号:
10504728 - 财政年份:2022
- 资助金额:
$ 81.73万 - 项目类别:
Develop AD Connectivity Maps with Human iPSC-Derived Brain Cells and their Use
使用人类 iPSC 衍生脑细胞开发 AD 连接图及其用途
- 批准号:
10686182 - 财政年份:2022
- 资助金额:
$ 81.73万 - 项目类别:
Study Susceptibility and Resistance to ApoE4 in Alzheimer's Disease
研究阿尔茨海默病中 ApoE4 的易感性和耐药性
- 批准号:
10418144 - 财政年份:2022
- 资助金额:
$ 81.73万 - 项目类别:
Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease
解读阿尔茨海默病神经网络功能障碍的多因素病因
- 批准号:
10525204 - 财政年份:2021
- 资助金额:
$ 81.73万 - 项目类别:
Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease
解读阿尔茨海默病神经网络功能障碍的多因素病因
- 批准号:
10670331 - 财政年份:2021
- 资助金额:
$ 81.73万 - 项目类别:
Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease
解读阿尔茨海默病神经网络功能障碍的多因素病因
- 批准号:
10691620 - 财政年份:2021
- 资助金额:
$ 81.73万 - 项目类别:
Project 1: Differential Roles of ApoE Isoforms in Neural Network Dysfunction of Alzheimer's Disease
项目 1:ApoE 同工型在阿尔茨海默病神经网络功能障碍中的不同作用
- 批准号:
10461842 - 财政年份:2021
- 资助金额:
$ 81.73万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 81.73万 - 项目类别:
Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease
解读阿尔茨海默病神经网络功能障碍的多因素病因
- 批准号:
10461839 - 财政年份:2021
- 资助金额:
$ 81.73万 - 项目类别:
Project 1: Differential Roles of ApoE Isoforms in Neural Network Dysfunction of Alzheimer's Disease
项目 1:ApoE 同工型在阿尔茨海默病神经网络功能障碍中的不同作用
- 批准号:
10670337 - 财政年份:2021
- 资助金额:
$ 81.73万 - 项目类别:
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