Development of Platelet-Derived Exercise Mimetics as a Treatment for Alzheimer's Disease and Alzhimer's Disease Related Dementias

PROJECT SUMMARY Despite the growing number of adults that are living with Alzheimer’s disease (AD) worldwide, there still lacks disease modifying treatments. Physical activity and exercise mitigate AD risk and boosts cognitive functions in patients, yet over a quarter of the elderly do not meet these activity guidelines, often due to physical limitations and resource constraints. Current therapeutic approaches focused on AD are restricted to targeting neuropathology within the central nervous system. Thus, there is an imperative need to develop alternative therapies that confer benefits of exercise to AD patients, circumventing their physical limitations. Prior work by our research team identified an exercise-induced platelet-derived factors in blood plasma that mediates the neurogenic and cognitive benefits of exercise in aged mice. Systemically increasing this blood based exercise mimetic conferred beneficial effects of exercise on cognitive function and AD-related neuropathology in aged mice and mouse models of AD pathology. The purpose of this study is to translate the scientific discoveries identifying this platelet-derived exercise mimetic as novel potential therapeutic to treat AD and related dementias. This is a Fast- Track Phase I to Phase II proposal that in Phase I aims to (1) generate various clones of the platelet-derived exercise mimetic with decreased safety risks and retained function, (2) optimization of the expression and purification of this platelet-derived exercise mimetic and (3) demonstrate that the protein engineered platelet-derived exercise mimetic can confer improved cognitive function in aged mice and a mouse model of AD pathology. In Phase II, we aim to (4) perform exploratory toxicity studies to better understand the therapeutic window and (5) begin CMC process development in support of IND-enabling studies.