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

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $431,750

## Abstract

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.

## Key facts

- **NIH application ID:** 10055667
- **Project number:** 1R21AG069067-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Wendy Liu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,750
- **Award type:** 1
- **Project period:** 2020-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055667

## Citation

> US National Institutes of Health, RePORTER application 10055667, Regulation of microglia by tissue stiffness and Piezo1 in Alzheimer's disease (1R21AG069067-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10055667. Licensed CC0.

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