Gender-dependent APOE4 regulation of neutrophil-microglia crosstalk in Alzheimer's disease

APOE 4是晚发性阿尔茨海默病（LOAD）最强的遗传风险因素。人类APOE的作用 AD中的变体在小胶质细胞和星形胶质细胞的调节中被广泛研究，但在中性粒细胞中没有。 APOE也在中性粒细胞中表达并控制其活化。此外，中性粒细胞已被证明 通过诱导小胶质细胞增生在AD小鼠中起负作用。因此，一个关键问题是APOE变异体是否 来源于嗜中性粒细胞控制由小胶质细胞驱动的免疫应答并促进疾病进展。 我们的长期目标是确定APOE信号在调节嗜中性粒细胞-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中起作用。我们做出了 以下初步观察：1）在AD和tau小鼠中小胶质细胞中诱导APOE表达， 与从稳态（M0）到神经变性小胶质细胞（MGnD）的表型转换相关; 2）APOE 4 驱动中性粒细胞中的神经退行性特征; 3）募集的APOE 4-中性粒细胞促进MGnD-小胶质细胞 APP/PS1和P301 S小鼠。基于这些发现，我们假设APOE 4炎症性 嗜中性粒细胞促进MGnD-小胶质细胞并加速AD中的神经变性和认知下降。我们 将在以下目标中阐述我们的假设： 目的1：确定中性粒细胞中的APOE变体如何影响小胶质细胞。我们建议：（1）界定 嗜中性粒细胞中APOE变体在嗜中性粒细胞-小胶质细胞串扰调节中的作用;和2）确定是否 用APOE 2/3中性粒细胞替换APOE 4中性粒细胞将恢复小胶质细胞的神经保护功能。 目的2：确定小胶质细胞中APOE变异体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向脑的募集; 和2）研究AD和tau小鼠模型脑中小胶质细胞和中性粒细胞的空间分布。 目的3：确定APOE变体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）鉴定从APOE e2、e3和e4 AD携带者中分离的人中性粒细胞， 它们直接调节iPSC-小胶质细胞中的MGnD特征;和2）研究iPSC-小胶质细胞空间结构， 人APOE e2、e3和e4 AD携带者在AD脑中的相互作用。 总之，靶向APOE-中性粒细胞-小胶质细胞轴可能提供一种新的治疗方法， 调节AD和痴呆中的先天免疫。

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.