Gender-dependent APOE4 regulation of neutrophil-microglia crosstalk in Alzheimer's disease
阿尔茨海默病中中性粒细胞-小胶质细胞串扰的性别依赖性 APOE4 调节
基本信息
- 批准号:10552667
- 负责人:
- 金额:$ 69.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:APP-PS1AccelerationAcuteAffectAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease patientAlzheimer&aposs disease riskApolipoprotein EAreaAstrocytesBasic ScienceBloodBrainBrain DiseasesCellsChronicClinicDataDementiaDiseaseDisease ProgressionDisease associated microgliaFemaleGenderGeneticGenotypeGliosisGoalsHumanImmune responseImmunityImpaired cognitionIn VitroInfiltrationInflammatoryInflammatory ResponseInvestigationLate Onset Alzheimer DiseaseMacrophageMediatingMemory impairmentMeta-AnalysisMicrogliaModelingMusNatural ImmunityNerve DegenerationNeurodegenerative DisordersNeutrophil InfiltrationOnset of illnessOutcomePeripheralPhenotypePlayProtein IsoformsRegulationResearchResolutionRiskRoleSamplingSenile PlaquesSignal TransductionSpatial DistributionTransgenic MiceTranslatingVariantapolipoprotein E-4brain cellcerebral atrophycognitive functiongenetic risk factorgenome-wideimmunoregulationimprovedin vivo Modelinduced pluripotent stem cellinnate immune functioninnate immune pathwaysinsightmalemouse modelneurodegenerative phenotypeneuroinflammationneuroprotectionneutrophilnovelnovel therapeutic interventionrecruitrisk variantsextau Proteinstooltrend
项目摘要
APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). The role of human APOE
variants in AD has been studied extensively in the regulation of microglia and astrocytes but not in neutrophils.
APOE is also expressed in neutrophils and controls their activation. Moreover, neutrophils have been shown to
play a negative role in AD mice via the induction of microgliosis. Thus, a key question is whether APOE variants
derived from neutrophils control immune responses driven by microglia and contribute to disease progression.
Our long-term goal is to define the role of APOE signaling in regulation neutrophil-microglia interactions in
neurodegeneration and determine which phenotypes and functions play a role in AD. We made the
following preliminary observations: 1) Induction of APOE expression in microglia in AD and tau mice is
associated with a phenotype switch from homeostatic (M0) to neurodegenerative microglia (MGnD); 2) APOE4
drives a neurodegenerative signature in neutrophils; 3) Recruited APOE4-neutrophils promote MGnD-microglia
in APP/PS1 and P301S mice. Based on these findings, we hypothesize that APOE4 inflammatory
neutrophils promote MGnD-microglia and accelerate neurodegeneration and cognitive decline in AD. We
will address our hypothesis in the following aims:
Aim 1: Define how APOE variants in neutrophils affects microglia. We propose to 1) Define the role of
APOE variants in neutrophils in the regulation of neutrophil-microglia crosstalk; and 2) Determine whether
replacement of APOE4 neutrophils with APOE2/3 neutrophils will restore microglial neuroprotective functions.
Aim 2: Define the impact of APOE variants in microglia on neutrophil recruitment to the diseased brain.
We will 1) Determine whether APOE variants modulate microglia to induce recruitment of neutrophils to the brain;
and 2) Investigate the spatial distribution of microglia and neutrophils in the brain of AD and tau mouse models.
Aim 3: Define the role of APOE variants in human neutrophils and their impact on human microglia in
AD. We propose to 1) Characterize human neutrophils isolated from APOE e2, e3 and e4 AD carriers and whether
they directly regulate the MGnD signature in iPSC-microglia; and 2) Investigate the neutrophil-microglia spatial
interactions in AD brain of human APOE e2, e3 and e4 AD carriers.
IN SUMMARY, targeting the APOE-neutrophil-microglia axis may provide a novel approach for therapeutic
modulation of innate immunity in AD and dementia.
APOE4是迟发性阿尔茨海默病(LOAD)最强的遗传危险因素。人类APOE的作用
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 }}
Oleg Butovsky其他文献
Oleg Butovsky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('Oleg Butovsky', 18)}}的其他基金
Role of a novel risk loci HAVCR2 of late-onset Alzheimer's disease in the regulation of microglial response in neurodegeneration
迟发性阿尔茨海默病的新风险位点 HAVCR2 在调节神经退行性小胶质细胞反应中的作用
- 批准号:
10608400 - 财政年份:2023
- 资助金额:
$ 69.48万 - 项目类别:
Gender-dependent APOE4 regulation of neutrophil-microglia crosstalk in Alzheimer's disease
阿尔茨海默病中中性粒细胞-小胶质细胞串扰的性别依赖性 APOE4 调节
- 批准号:
10344242 - 财政年份:2022
- 资助金额:
$ 69.48万 - 项目类别:
APOE e4 negative regulation of microglia-astrocytes crosstalk in Alzheimer's disease
APOE e4 对阿尔茨海默病中小胶质细胞-星形胶质细胞串扰的负调节
- 批准号:
10429190 - 财政年份:2022
- 资助金额:
$ 69.48万 - 项目类别:
Xenon gas treatment to modulate microglia in neurodegenerative diseases
氙气治疗调节神经退行性疾病中的小胶质细胞
- 批准号:
10617078 - 财政年份:2021
- 资助金额:
$ 69.48万 - 项目类别:
Xenon gas treatment to modulate microglia in neurodegenerative diseases
氙气治疗调节神经退行性疾病中的小胶质细胞
- 批准号:
10259094 - 财政年份:2021
- 资助金额:
$ 69.48万 - 项目类别:
Targeting the miR-155 and APOE-TREM2 pathways to restore dysfunctional microglia in Alzheimer's disease
靶向 miR-155 和 APOE-TREM2 通路以恢复阿尔茨海默病中功能失调的小胶质细胞
- 批准号:
9926784 - 财政年份:2017
- 资助金额:
$ 69.48万 - 项目类别:
Targeting the miR-155 and APOE-TREM2 pathways to restore dysfunctional microglia in Alzheimer’s disease
靶向 miR-155 和 APOE-TREM2 通路以恢复阿尔茨海默病中功能失调的小胶质细胞
- 批准号:
9219386 - 财政年份:2017
- 资助金额:
$ 69.48万 - 项目类别:
Microglial mechanisms of postoperative CNS inflammation and cognitive decline
术后中枢神经系统炎症和认知能力下降的小胶质细胞机制
- 批准号:
9010611 - 财政年份:2016
- 资助金额:
$ 69.48万 - 项目类别:
Restoration of homeostatic microglia in CNS inflammation
中枢神经系统炎症中小胶质细胞稳态的恢复
- 批准号:
10426253 - 财政年份:2014
- 资助金额:
$ 69.48万 - 项目类别:
相似海外基金
EXCESS: The role of excess topography and peak ground acceleration on earthquake-preconditioning of landslides
过量:过量地形和峰值地面加速度对滑坡地震预处理的作用
- 批准号:
NE/Y000080/1 - 财政年份:2024
- 资助金额:
$ 69.48万 - 项目类别:
Research Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328975 - 财政年份:2024
- 资助金额:
$ 69.48万 - 项目类别:
Continuing Grant
SHINE: Origin and Evolution of Compressible Fluctuations in the Solar Wind and Their Role in Solar Wind Heating and Acceleration
SHINE:太阳风可压缩脉动的起源和演化及其在太阳风加热和加速中的作用
- 批准号:
2400967 - 财政年份:2024
- 资助金额:
$ 69.48万 - 项目类别:
Standard Grant
Market Entry Acceleration of the Murb Wind Turbine into Remote Telecoms Power
默布风力涡轮机加速进入远程电信电力市场
- 批准号:
10112700 - 财政年份:2024
- 资助金额:
$ 69.48万 - 项目类别:
Collaborative R&D
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328973 - 财政年份:2024
- 资助金额:
$ 69.48万 - 项目类别:
Continuing Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328972 - 财政年份:2024
- 资助金额:
$ 69.48万 - 项目类别:
Continuing Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
- 批准号:
2332916 - 财政年份:2024
- 资助金额:
$ 69.48万 - 项目类别:
Standard Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
- 批准号:
2332917 - 财政年份:2024
- 资助金额:
$ 69.48万 - 项目类别:
Standard Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328974 - 财政年份:2024
- 资助金额:
$ 69.48万 - 项目类别:
Continuing Grant
Study of the Particle Acceleration and Transport in PWN through X-ray Spectro-polarimetry and GeV Gamma-ray Observtions
通过 X 射线光谱偏振法和 GeV 伽马射线观测研究 PWN 中的粒子加速和输运
- 批准号:
23H01186 - 财政年份:2023
- 资助金额:
$ 69.48万 - 项目类别:
Grant-in-Aid for Scientific Research (B)














{{item.name}}会员




