Regulation of microglia by tissue stiffness and Piezo1 in Alzheimer's disease

项目总结/摘要 阿尔茨海默病（AD）的标志性病理指标之一是阿尔茨海默病（AD）的累积。 淀粉样斑块或β淀粉样致密灶部位的小胶质细胞。小胶质细胞是主要的 常驻先天免疫细胞的大脑，并发挥主要作用，在大脑的稳态，通过 突触修剪，健康的淀粉样蛋白β周转，以及推进和解决炎症 应答这些细胞与几乎所有的神经退行性疾病有关， 因此，了解他们的微环境如何影响健康和病理功能， 至关重要。这个探索性项目的目标是研究组织的潜在作用 在AD期间，淀粉样蛋白斑块的沉积改变了硬度， 小胶质细胞功能研究人员以前的工作表明，刚度调节了 单核细胞衍生的巨噬细胞，一种密切相关的先天免疫细胞的功能。更硬 底物增强细胞因子的产生以响应炎性刺激物如LPS 通过机械敏感钙渗透离子通道Piezo 1。在此，我们建议 研究刚度和Piezo 1在小胶质细胞功能中的作用， Piezo 1基因缺失的小胶质细胞和嵌合动物模型。在目标1中，我们将使用 工程化培养基质，以研究刚度对Piezo 1活性的影响，以及 对小胶质细胞炎症、迁移和吞噬行为的下游作用。在目标2中， 将细胞移植到人源化AD小鼠体内，研究小胶质细胞植入， 斑块和体内炎症。总之，这些研究将调查一个新的作用， AD进展过程中小胶质细胞中硬度和Piezo 1的功能。

PROJECT SUMMARY / ABSTRACT One of the hallmark pathological indicators of Alzheimer’s disease (AD) is the accumulation of microglia at sites of amyloid plaques or dense foci of amyloid beta. Microglia are the primary resident innate immune cells of the brain and play a major role in brain homeostasis through synaptic pruning, healthy amyloid beta turnover, and advancing and resolving inflammatory responses. These cells have been implicated in almost all neurodegenerative diseases, and thus understanding how their microenvironment influences healthy and pathological function is critically important. The goal of this exploratory project is to examine the potential role of tissue stiffness, which is altered by the deposition of amyloid plaques during AD, in regulation of microglia function. Previous work from the investigator has shown that stiffness modulates the function of monocyte-derived macrophages, a closely related innate immune cell. Stiffer substrates enhance the production of cytokines in response to inflammatory stimuli such as LPS through the mechanosensitive calcium permeable ion channel Piezo1. Here, we propose to study the role of stiffness and Piezo1 in microglia function using human stem cell-derived microglia with Piezo1 genetically depleted and a chimeric animal model. In Aim 1, we will use engineered culture substrates to investigate the effects of stiffness on Piezo1 activity, and downstream effects on microglia inflammatory, migratory, and phagocytic behavior. In Aim 2, we will transplant cells into humanized AD mouse to study microglia engraftment, association with plaques, and inflammation in vivo. Together, these studies will investigate a novel role for stiffness and Piezo1 in microglia function during AD progression.