Developing blood-based exercise mimetic as a treatment for Alzheimer's disease and 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 Glycosylphosphatidylinositol-Specific Phospholipase D1 (Gpld1) an exercise-induced circulating factor in blood plasma that mediates the neurogenic and cognitive benefits of exercise in aged mice and shows neurobehavioral relevance in elderly human adults. Systemically increasing Gpld1 levels in blood mimicked the 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 peripheral targets in blood – GPLD1 in particular – as novel potential therapeutic blood-based exercise mimetics to treat AD- related dementias. We will achieve this with Three Specific Aims: 1: Identify three lead recombinant human GPLD1 molecules. 2: Establish optimal exposure through extensive in vivo PK profiling in aged wild type mice of the three lead recombinant human GPLD1 molecules. 3: Test one primary and one alternate lead recombinant human GPLD1 molecule for disease modification in the 5xFAD mouse model of AD pathology. Successful completion of these aims is the critical first step for the identification and commercialization of potential therapeutic blood- based exercise mimetics to treat AD-related dementias.