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

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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.