Targeting age-related endosome dysfunction to treat cognitive decline and Alzheimer's disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a growing humanitarian and economic burden. Advanced age is the greatest risk factor for AD so the long- term goal of this research is to better understand how advancing age contributes to AD occurrence and progression. Aging and AD pathology are characterized by a decline in the cell’s ability to eliminate damaged and pathological proteins through endosome trafficking (NOT- 21-034) which contributes to the accumulation of protein like tau within neurons and other cells of the brain. We have identified a key protein involved in the formation of endosomes, the vehicle for endosome trafficking, that is decreased in neurons across the lifespan and further decreased in neurons from donors with AD. We have shown that we can restore expression of this protein in patient-derived human neurons using adeno-associated virus (AAV) and that this decreases intracellular tau. Based on these findings, the Specific Aims of this proposal are to: 1) determine how increasing endosome formation decreases tau in neurons and 2) define how increasing endosome formation influences cognition and AD pathology in transgenic and aged wild type mice. If successful, these studies will establish decreased endosome formation as a cause of tau pathology in AD and support the development of therapeutic strategies to enhance endosome formation for the treatment of AD and other proteinopathies (i.e., frontotemporal dementia, Parkinson’s disease and others).