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 是晚发性阿尔茨海默病 (LOAD) 的最强遗传风险因素。人类 APOE 的作用。 AD 变异在小胶质细胞和星形胶质细胞的调节中已得到广泛研究，但在中性粒细胞中的调节尚未得到广泛研究。 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具有这种功能。 APOE 变异是否通过诱导小胶质细胞增生在 AD 小鼠中发挥负面作用。源自中性粒细胞控制由小胶质细胞驱动的免疫反应并促进疾病进展。我们的长期目标是确定 APOE 信号在调节中性粒细胞 - 小胶质细胞相互作用中的作用神经退行性变并确定哪些表型和功能在 AD 中发挥作用。初步观察结果如下： 1) AD 和 tau 小鼠小胶质细胞中 APOE 表达的诱导是与从稳态 (M0) 到神经退行性小胶质细胞 (MGnD) 的表型转换相关；2) APOE4 3) 招募的 APOE4-中性粒细胞促进 MGnD-小胶质细胞基于这些发现，我们在 APP/PS1 和 P301S 小鼠中捕获了 APOE4 炎症。中性粒细胞促进 MGnD-小胶质细胞并加速 AD 中的神经退行性变和认知能力下降。将在以下目标中解决我们的假设：目标 1：定义中性粒细胞中的 APOE 变异如何影响小胶质细胞我们建议 1) 定义 APOE 的作用。中性粒细胞中的 APOE 变异对中性粒细胞-小胶质细胞串扰的调节；以及 2) 确定是否用 APOE2/3 中性粒细胞替换 APOE4 中性粒细胞将恢复小胶质细胞的神经保护功能。目标 2：确定小胶质细胞中 APOE 变异对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以诱导中性粒细胞招募至大脑； 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 变异在人类中性粒细胞中的作用及其对人类小胶质细胞的影响 AD。我们建议 1) 表征从 APOE e2、e3 和 e4 AD 携带者中分离的人类中性粒细胞，以及是否它们直接调节 iPSC-小胶质细胞中的 MGnD 特征；2) 研究中性粒细胞-小胶质细胞空间人类 APOE e2、e3 和 e4 AD 携带者 AD 大脑中的相互作用。总之，靶向 APOE-中性粒细胞-小胶质细胞轴可能为治疗提供一种新方法。 AD 和痴呆症中先天免疫的调节。