Investigating the platelet response in mouse models of VCID - Project Summary/Abstract Vascular contributions to cognitive impairment and dementia (VCID) are a significant yet underexplored factor in dementia pathology, frequently coexisting with Alzheimer’s disease (AD). While pericytes, astrocytes, and microglia have been studied for their roles in cerebrovascular damage, platelets—typically found beyond the blood-brain barrier—may also contribute to vascular dysfunction. Platelets drive endothelial injury through pro- inflammatory signaling, extracellular matrix degradation, and thrombotic activity, yet their role in cerebrovascular decline remains unclear. Given their accessibility and known involvement in vascular disease, targeting platelets may provide a novel therapeutic avenue for VCID, an area currently lacking effective treatments. This proposal aims to investigate platelet-mediated mechanisms of vascular injury in VCID and determine whether inhibiting platelet surface receptor function can mitigate disease progression. We hypothesize that platelets adopt a hyperactive, pro-inflammatory phenotype that exacerbates cerebrovascular dysfunction and that inhibiting platelet glycoprotein VI (GPVI) signaling will alleviate these effects. To test this, we will assess platelet activation and vascular interactions over time in two VCID mouse models: diet-induced hyperhomocysteinemia (HHcy) and amyloidogenic Tg2576 mice. Using flow cytometry, multiphoton imaging, and histological analyses, we will characterize platelet activation states, surface receptor expression, and their infiltration into cerebrovascular structures. Additionally, we will determine whether GPVI depletion reduces platelet-driven vascular damage and inflammation, thereby improving cognitive and physiological outcomes. The successful completion of these aims will provide crucial insights into the overlooked contributions of platelets to VCID pathology and establish their potential as therapeutic targets. Furthermore, this project will enhance my technical expertise in neurovascular imaging, histology, RNAseq, and mouse modeling of neurovascular disease while contributing to my professional development as an independent researcher. With the resources available at Indiana University – Indianapolis, including the Alzheimer’s Disease Research Center and mentorship from Dr. Wilcock, this proposal will advance both scientific knowledge and my career trajectory in dementia-related research.
