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：
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/10552667
关键词：
APP-PS1 Acceleration Acute Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos s disease risk Apolipoprotein E Area Astrocytes Basic Science Blood Brain Brain Diseases Cells Chronic Clinic Data Dementia Disease Disease Progression Disease associated microglia Female Gender Genetic Genotype Gliosis Goals Human Immune response Immunity Impaired cognition In Vitro Infiltration Inflammatory Inflammatory Response Investigation Late Onset Alzheimer Disease Macrophage 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 Senile Plaques Signal Transduction Spatial Distribution Transgenic Mice Translating Variant apolipoprotein E-4 brain cell cerebral atrophy cognitive function genetic risk factor genome-wide immunoregulation improved in vivo Model induced pluripotent stem cell innate immune function innate immune pathways insight male mouse model neurodegenerative phenotype neuroinflammation neuroprotection 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.

APOE4是晚期发作的阿尔茨海默氏病（负载）的强大遗传危险因素。人类apoe的角色 AD中的变体已在小胶质细胞和星形胶质细胞的调节中进行了广泛研究，但中性粒细胞的变体不进行。 ApoE还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，在AD小鼠中起负面作用。那是一个关键问题是apoe变体源自中性粒细胞控制由小胶质细胞驱动并导致疾病进展的免疫复杂。我们的长期目标是定义APOE信号在调节中性粒细胞 - 丝状相互作用中的作用神经变性并确定哪些表型和功能在AD中起作用。我们做了遵循初步观察：1）AD和TAU小鼠中小胶质细胞中APOE表达的诱导是与表型从体内平衡（M0）转换为神经退行性小胶质细胞（MGND）相关； 2）APOE4 在中性粒细胞中驱动神经退行性签名； 3）招募的APOE4-中性噬细胞促进MGND-Microglia 在App/PS1和P301S小鼠中。基于这些发现，我们假设APOE4炎症中性粒细胞促进MGND-Microglia并加速AD的神经退行性和认知能力下降。我们将在以下目的中解决我们的假设： AIM 1：定义中性粒细胞中的APOE变体如何影响小胶质细胞。我们建议1）定义中性粒细胞中嗜中性粒细胞 - 麦片串扰的apoe变体； 2）确定是否用APOE2/3中性粒细胞代替APOE4中性粒细胞将恢复小胶质神经保护功能。 AIM 2：定义APOE变体在小胶质细胞中对嗜中性粒细胞募集到患病大脑的影响。我们将1）确定APOE变体是否调节小胶质细胞诱导嗜中性粒细胞募集到大脑； 2）研究AD和Tau小鼠模型大脑中小胶质细胞和中性粒细胞的空间分布。目标3：定义APOE变体在人类嗜中性粒细胞中的作用及其对人类小胶质细胞的影响广告。我们建议1）从APOE E2，E3和E4 AD携带者中分离出的人类嗜中性粒细胞，以及是否是否它们直接调节IPSC-Microglia中的MGND签名；和2）研究中性粒细胞 - 微神经空间人类APOE E2，E3和E4 AD载体的AD大脑中的相互作用。总而言之，针对APOE-中性磷脂 - 丝状轴可能会提供一种新型的治疗方法 AD和痴呆症中先天免疫的调节。