Role of Protease Activated Receptor 4 in cerebrovascular dysfunction and dementia

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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.