Pathway maps of platelet phenotype and function

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ABSTRACT FOR ADMINISTRATIVE SUPPLEMENT Platelets are specialized peripheral blood cells that rapidly engage and resolve endothelial injury through adhesion, secretion and aggregation responses. These regulated changes in platelet form and function are essential to hemostasis and vascular health, but also support acute and chronic pathologies of aging (i.e., thrombosis, atherosclerosis).Translational efforts aiming to determine disease-specific platelet activities have identified heterogeneous platelet phenotypes in the laboratory as well as in the clinic associated with acute thrombotic and chronic inflammatory conditions – including vascular pathologies in Alzheimer’s disease and related dementias (AD/ADRD). The mechanisms by which maladaptive platelet phenotypes arise in disease are unclear. Efforts to develop effective therapeutic, diagnostic and preventive strategies focused on maladaptive platelets in aging and vascular diseases remain to be actualized. In this Administrative Supplement, we aim to determine how Alzheimer’s disease etiology relates to alterations in molecular programs of platelets that support inflammatory and thrombotic responses associated with disease. Our central hypothesis is that signaling systems underlying platelet cell physiological responses are specifically dysregulated in Alzheimer’s disease in a manner promoting as well as marking disease progression. As a supplement to our parent award, this study will make further use of a high-throughput, proteomics-based workflow to measure and map intracellular signaling events in platelets isolated from donors with Alzheimer’s disease relative to platelets from age and sex matched mild cognitive impairment (MCI) and normal cognition (NC) control donors. In collaboration with clinicians and researchers from the NIA P30-supported Oregon Alzheimer’s Disease Center (OADC), our multidisciplinary team will systematically define how Alzheimer’s disease relates to alterations in intracellular signaling events that orchestrate platelet adhesion (Aim 1), secretion (Aim 2) and aggregation (Aim 3) in the context of vascular inflammation and Alzheimer’s disease progression. As a major goal of the parent award is to determine how maladaptive platelet phenotypes develop, and, ultimately, how they may be targeted and managed, this Supplement provides a unique opportunity to add value to ongoing studies while advancing Alzheimer’s disease research with state-of-the-art methods. Ultimately, this work will generate knowledge as well as a conceptual means to understand how to better predict, detect and manage Alzheimer’s disease.