# Role of Protease Activated Receptor 4 in cerebrovascular dysfunction and dementia

> **NIH NIH R21** · VANDERBILT UNIVERSITY · 2021 · $218,549

## Abstract

We propose to study the role of protease-activated receptor (PAR) 4 in contributing to vascular cognitive
impairment and dementia (VCID). Because traumatic brain injury is a major risk factor for AD, wounding-induced
platelet activation and thrombin are at the top of a chain of events leading to fibrin deposition, microinfarcts,
blood-brain barrier disruption and inflammation that may contribute to VCID. PAR4 is a platelet GPCR that is
strongly activated by thrombin and only slowly inactivated, and thus contributes most of the platelet-derived
thrombin, greater procoagulant microparticle formation, increased fibrin deposition, and initiation of platelet-
stimulated inflammation. PAR4 is also expressed in immune cells and vasculature, and under inflammatory
conditions, PAR4 is overexpressed via epigenetic demethylation of the PAR4 gene, F2RL3. PAR4 knockout
studies have determined a role for PAR4 in hemostasis and thrombosis, as well as in neutrophil homing and
invasion at the site of vascular insult. We have shown that higher levels of PAR4 expression in the prefrontal
cortex of aging adults were associated with a faster rate of cognitive decline in a longitudinal human cohort
evaluating cognitive aging, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP).
We also found that PAR4 is upregulated on cerebral arterioles in 5XFAD mice that express a suite of 5 mutations
associated with familial AD. However, a direct test of the role of PAR4 in vascular dementia and AD pathology
has never been carried out previously. In this grant, we will study the role of PAR4 both in the brains of aging
humans with dementia as well as in 5XFAD mice. In Aim 1, we propose to explore the role of PAR4 human
genetic variation, postmortem brain expression, and postmortem brain epigenetic alterations in the
neuropathology and clinical progression of AD and VCID. In Aim 2, we will cross PAR4-/- mice with 5XFAD mice
to determine if lack of PAR4 will protect against fibrin deposition and inflammation and enhance cognition. In As
sex differences are present in longevity/aging, inflammation and immunity, vascular disease and dementia, all
studies will be performed in both sexes. If overexpression of PAR4 increases the progression of dementia, and
deletion of PAR4 can arrest or slow the development of dementia in the severe animal model 5XFAD, this will
suggest that pharmacological inhibition of PAR4 might be a useful approach therapeutically, suggesting a much
more in-depth evaluation of PAR4 as a pharmacological target in humans. A key role of PAR4 at the beginning
of the cascade of platelet activation and initiation of inflammation would make it an excellent target for treatment
of AD and vascular dementia.

## Key facts

- **NIH application ID:** 10287131
- **Project number:** 1R21AG073891-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** HEIDI E HAMM
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $218,549
- **Award type:** 1
- **Project period:** 2021-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10287131

## Citation

> US National Institutes of Health, RePORTER application 10287131, Role of Protease Activated Receptor 4 in cerebrovascular dysfunction and dementia (1R21AG073891-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10287131. Licensed CC0.

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