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.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
YADONG HUANG其他文献
YADONG HUANG的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
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:
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:
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:
相似国自然基金
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
- 批准号:JCZRQN202500010
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
- 批准号:2025JJ70209
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
- 批准号:
- 批准年份:2024
- 资助金额:0 万元
- 项目类别:面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
- 批准号:2023JJ50274
- 批准年份:2023
- 资助金额:0.0 万元
- 项目类别:省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
- 批准号:n/a
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
- 批准号:81973577
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
- 批准号:81602908
- 批准年份:2016
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
- 批准号:81501928
- 批准年份:2015
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Determining the mechanism of action of cis-acting modifiers on the age of onset of Huntington Disease
确定顺式作用修饰剂对亨廷顿病发病年龄的作用机制
- 批准号:
417256 - 财政年份:2019
- 资助金额:
$ 81.73万 - 项目类别:
Studentship Programs
Effect of age of onset of contraception use on brain functioning.
避孕开始年龄对大脑功能的影响。
- 批准号:
511267-2017 - 财政年份:2017
- 资助金额:
$ 81.73万 - 项目类别:
University Undergraduate Student Research Awards
Non-random occurrence and early age of onset of diverse lymphoid cancers in families supports the existence of genetic risk factors for multiple lymphoid cancers.
家族中多种淋巴癌的非随机发生和发病年龄较早,支持多种淋巴癌存在遗传危险因素。
- 批准号:
347105 - 财政年份:2016
- 资助金额:
$ 81.73万 - 项目类别:
Polish-German Child Bilingualism: The Role of Age of Onset for Long-Term Achievement
波兰-德国儿童双语:发病年龄对长期成就的作用
- 批准号:
277135691 - 财政年份:2015
- 资助金额:
$ 81.73万 - 项目类别:
Research Grants
Bioinformatics strategies to relate age of onset with gene-gene interaction
将发病年龄与基因间相互作用联系起来的生物信息学策略
- 批准号:
9097781 - 财政年份:2015
- 资助金额:
$ 81.73万 - 项目类别:
Early Age-of-Onset AD: Clinical Heterogeneity and Network Degeneration
早期 AD 发病年龄:临床异质性和网络退化
- 批准号:
9212684 - 财政年份:2014
- 资助金额:
$ 81.73万 - 项目类别:
Early Age-of-Onset AD: Clinical Heterogeneity and Network Degeneration
早期 AD 发病年龄:临床异质性和网络退化
- 批准号:
8696557 - 财政年份:2014
- 资助金额:
$ 81.73万 - 项目类别:
Effects of delaying age of onset of binge drinking on adolescent brain development: A proposal to add neuroimaing measures to the CO-Venture Trial.
延迟酗酒的发病年龄对青少年大脑发育的影响:在 CO-Venture 试验中添加神经影像测量的建议。
- 批准号:
267251 - 财政年份:2012
- 资助金额:
$ 81.73万 - 项目类别:
Operating Grants
Stress Effects on Alcohol Consumption: Age of onset and genes in heavy drinkers
压力对饮酒的影响:酗酒者的发病年龄和基因
- 批准号:
8606722 - 财政年份:2012
- 资助金额:
$ 81.73万 - 项目类别:
Marijuana: Neurobiologic Correlates of Age of Onset
大麻:发病年龄的神经生物学相关性
- 批准号:
8644793 - 财政年份:2012
- 资助金额:
$ 81.73万 - 项目类别: