PROJECT SUMMARY/ABSTRACT: Amyloid beta (Aβ) is the hallmark of Alzheimer’s disease (AD) but also affects Parkinson’s disease (PD) patients, especially in later stages when PD dementia (PDD) starts to develop. When PDD advances, about 50% of PDD patients develop extensive neuropathology similar to AD. This includes misfolded Aβ plaques and tau neurofibrillary tangles, while the source and scale of Aβ-produced damage and its effects on PDD development are unknown. In 53% of PD patients there is also an accumulation of insoluble Aβ amyloid around blood vessels, known as cerebral amyloid angiopathy (CAA). We previously found that systemic Aβ peptide, generated by blood platelets during cerebral thrombosis, is highly visible on and around the blood vessels within the brain. In addition, in a murine model of PD, when chemicals are injected into the brain to kill dopaminergic neurons, Aβ appears on and around blood vessel walls. We hypothesized that tissue accumulation of Aβ and CAA in PD may be the result of continual platelet activation due to local brain inflammation, with high quantities of Aβ transported through blood vessel walls to brain tissue, causing injury. The objectives of this proposal are to find the platelet-related mechanisms involved in late- PD pathogenesis. Our specific aims will test whether the direct reduction of platelet count, platelet activation/degranulation, or blood plasma Aβ carriers are important in the development of Aβ accumulation. Our proposed innovative research will determine whether this direct approach is effective and could thereby lead to a cure for late-stage Aβ accumulation in PD. This approach might open the way for new therapeutics to stop the development of PDD, which would be a very significant contribution to public health.

PROJECT NARRATIVE: Parkinson’s disease (PD), late PD dementia (PDD), and PD-related amyloid angiopathy are looming disasters for public health. The combined direct and indirect cost of PD, including treatment, social security payments, and lost income, is estimated to be nearly $52 billion per year in the United States alone. Nearly 1 million Americans are living with PD (2020), and the numbers are growing, as there is no definitive cure. This proposed research is highly relevant, as the control of systemic β-amyloid peptide production and transport, involving platelets and blood, could slow the advance of late-stage dementia and open up a new approach to therapy.