# Modifying endothelial Piezo 1 function to improve brain perfusion in AD/ADRD

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $682,211

## Abstract

The following proposal is built on our recent novel findings showing a critical role for endothelial Piezo1 in cerebral blood
flow (CBF) regulation and brain health. Piezo1 is a mechanosensitive ion channel that gates Ca2+ and Na+ influx in response
to membrane stretch or increased shear force. In the peripheral vasculature, endothelial Piezo1 is activated by increased
flow/shear and promotes vasodilation through Ca2+-dependent mechanisms. We now provide novel preliminary data
demonstrating that selective loss of endothelial Piezo1 promotes a decrease in resting CBF (hypoperfusion), while
pharmacological activation of endothelial cell (EC) Piezo1 promotes increased CBF (hyperemia). Our data further show
that the consequences of chronic EC Piezo1 loss of function (LOF) include endothelial upregulation of genes associated
with inflammation and microglia/macrophage recruitment (scRNAseq), widespread microgliosis, and development of
white matter injury.
In specific regard to AD/ADRD, beta-amyloid (Ab) peptides (e.g. Ab40, Ab42) have been shown to acutely reduce Piezo1
sensitivity to flow/shear activation. These findings offer the intriguing possibility that conditions of amyloidosis may impair
EC Piezo1-mediated CBF regulation. Our preliminary data support this possibility, as we show progressive impairment of
EC Piezo1-dependent hyperemia in pre-symptomatic and symptomatic TgAPP mice. Additionally, by analyzing public
snRNAseq data from AD and cognitively normal patients, we found a transcriptional signature consistent with reduced
flow- and Piezo1-dependent signaling in EC from brain of AD patients. Together, these data suggest that EC Piezo1 is vital
for normal CBF regulation and that the dysfunction of EC Piezo1 can exacerbate cerebral hypoperfusion and worsen age
and Ab-driven pathology.
In the proposed project, we will define how EC Piezo1 LOF contributes to cerebrovascular pathology in aging and
amyloidosis and explore the novel strategy of EC Piezo1 gain of function (GOF) as an ameliorative solution. Our overall
hypothesis is that EC Piezo1 LOF potentiates aging and Ab-mediated pathology and that EC Piezo1 GOF can restore
cerebrovascular function and provide resilience to aging and Ab-mediated cognitive decline. Aim 1 will define how brain-
specific EC Piezo1 LOF leads to brain pathology in mouse models of aging and amyloidosis. We will use two TgAPP mouse
lines that model different aspects of amyloidosis (Tg2576 and TgSwDI). Aim 2 will leverage the ability to enhance CBF via
EC Piezo1 GOF to restore CBF regulation, provide cerebrovascular resilience, and slow progression of aging and Ab-related
brain pathology and cognitive decline in mouse models of aging and amyloidosis. We will induce Piezo1 GOF selectively in
brain endothelium of young and aged WT mice and in TgAPP mice at pre-symptomatic and symptomatic stages.
Completion of Aims 1 and 2 will employ a combination of in vivo measures of CBF and cerebrovascular function, measures
of EC Pi...

## Key facts

- **NIH application ID:** 10842317
- **Project number:** 5R01AG081942-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Sean P Marrelli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $682,211
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842317

## Citation

> US National Institutes of Health, RePORTER application 10842317, Modifying endothelial Piezo 1 function to improve brain perfusion in AD/ADRD (5R01AG081942-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10842317. Licensed CC0.

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