P1‐069: A PRESENILIN 1 MUTATION ALTERS APP LOCALIZATION IN HUMAN NEURONS

Presenilin 1 (PS1) is the catalytic core of the γ-secretase complex that cleaves the Amyloid Precursor Protein (APP) and other type 1 transmembrane proteins. Mutations in PS1 are the most common cause of early onset Alzheimer's disease (AD). Despite extensive research into the mechanisms by which PS1 mutations cause AD, there is still uncertainty in the precise mechanisms by which PS1 mutations initiate disease. We utilized isogenic induced pluripotent stem cell (iPSC) derived neurons that harbor the PS1 Δe9 mutation to investigate neuronal phenotypes caused by mutant PS1. Additionally, we used quantitative immunofluorescence to measure APP localization and APP colocalization with endocytic markers. We report that the PS1 Δe9 mutation alters localization of APP such that there is decreased APP in axons and increased APP in the cell body. Additionally we found that there is decreased colocalization of APP with the early enodcytic marker Rab5 in axons. Our results suggest that abnormal APP localization may be an early event in progression of familial AD.