Proteolysis refers to the breakdown of proteins into smaller polypeptides or amino acids. Two proteolytic products that are derived from the amyloid precursor protein, C99 and Amyloid Beta 42, play defining roles in Alzheimer’s disease. One angle for preventing Alzheimer’s disease clinically is to define how these APP-derived products, especially Amyloid Beta 42, accumulate in the brain and contribute to disease progression. Our research suggests that an increase in C99 deranges endosome structure and function. Endosomes are membrane-bound structures within a cell that are important for neuronal function and survival. Preliminary data raises the possibility that endosomal dysregulation may occur through an increase in C99 levels that occurs during processing by gamma-secretase. We aim to characterize the cellular consequences of lack of processing of gamma-secretase substrates, including C99. We will employ gamma-secretase modulators, discovered under Cure Alzheimer’s Fund and National Institutes of Health funding, to demonstrate the extent to which GSMs mitigate or prevent amyloid beta-mediated inhibition of gamma-secretase activity. Our studies promise unique insights into AD pathogenesis and the therapeutic utility of GSMs.