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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：
10344242
负责人：
Oleg Butovsky
金额：
$ 69.48万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
https://reporter.nih.gov/project-details/10344242
关键词：
APP-PS1 Acute Address Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-Protein Apolipoprotein E Area Astrocytes Basic Science Blood Brain Brain Diseases Cells Chronic Clinic Cognitive Data Disease Disease Progression Disease associated microglia Female Gender Genetic Genotype Goals Human Immune Immune response Immunity Impaired cognition In Vitro Inflammatory Inflammatory Response Investigation Late Onset Alzheimer Disease Mediating Memory impairment Meta-Analysis Microglia Modeling Mus Natural Immunity Nerve Degeneration Neurodegenerative Disorders Neutrophil Infiltration Onset of illness Outcome Peripheral Phenotype Play Protein Isoforms Regulation Research Resolution Risk Role Sampling Signal Transduction Spatial Distribution Transgenic Mice Translating Variant apolipoprotein E-4 base brain cell brain dysfunction genetic risk factor genome-wide improved in vivo Model induced pluripotent stem cell insight macrophage male mouse model neurodegenerative phenotype neuroinflammation neutrophil novel novel therapeutic intervention recruit risk variant sex tau Proteins tool trend

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.

载脂蛋白E4是晚发性阿尔茨海默病(LOAD)最强的遗传风险因素。人类载脂蛋白E的作用阿尔茨海默病的变异体在小胶质细胞和星形胶质细胞的调节中得到了广泛的研究，但在中性粒细胞中还没有得到广泛的研究。 APOE也在中性粒细胞中表达，并控制其激活。此外，中性粒细胞已被证明通过诱导小胶质细胞增多症对AD小鼠起到负性作用。因此，一个关键的问题是APOE的变种来源于中性粒细胞，控制由小胶质细胞驱动的免疫反应，并有助于疾病的进展。我们的长期目标是确定载脂蛋白E信号在调节中性粒细胞-小胶质细胞相互作用中的作用。并确定哪些表型和功能在阿尔茨海默病中起作用。我们做了 1)诱导AD和tau小鼠小胶质细胞APOE的表达与从稳态(M0)到神经退行性小胶质细胞(MGnD)的表型转换有关；2)载脂蛋白4 在中性粒细胞中驱动神经退行性改变；3)招募的APOE4-中性粒细胞促进MGnD-小胶质细胞 APP/PS1和P301S小鼠。基于这些发现，我们假设APOE4是炎症性的中性粒细胞促进MGnD-小胶质细胞，加速阿尔茨海默病的神经变性和认知功能下降。我们我将从以下几个方面阐述我们的假设：目的1：确定中性粒细胞中的载脂蛋白E变异如何影响小胶质细胞。我们建议1)定义中性粒细胞中APOE变异在调节中性粒细胞-小胶质细胞串扰中的作用；以及2)决定用APOE2/3中性粒细胞替代APOE4中性粒细胞将恢复小胶质细胞的神经保护功能。目的2：明确小胶质细胞内APOE变异对中性粒细胞向病变脑内募集的影响。我们将1)确定APOE变异体是否调节小胶质细胞以诱导中性粒细胞向脑内募集； 2)研究AD和tau小鼠模型脑内小胶质细胞和中性粒细胞的空间分布。目的3：明确载脂蛋白E变异体在人中性粒细胞中的作用及其对人小胶质细胞的影响。广告。我们建议1)鉴定从载脂蛋白E e2、e3和e4 AD携带者中分离的人中性粒细胞，以及它们直接调节IPSC-小胶质细胞中的MGnD信号；以及2)研究中性粒细胞-小胶质细胞的空间载脂蛋白E e2、e3和e4 AD携带者AD脑内相互作用的研究综上所述，靶向apoE-中性粒细胞-小胶质细胞轴可能为治疗提供一种新的途径。阿尔茨海默病和痴呆的天然免疫调节。