Genetics and neuropathology of Alzheimer’s disease clearly point to the importance for pathogenesis of decreased gamma-secretase-mediated processing of the amyloid precursor protein with consequent increased levels of long, aggregation-prone amyloid beta peptides. Recent research has provided evidence that the disease develops as a vicious cycle of impaired function of gamma-secretase, increased generation of aggregation-prone amyloid beta and accumulation of uncleaved gamma-secretase substrates with compromise of multiple cell-signaling pathways. Nevertheless, the nature of the most toxic amyloid beta species, as well as the details of the molecular and cellular consequences of their altered production, remain unclear. Lack of a thorough understanding of the disease pathomechanisms hinders therapeutic development. Our novel, exciting data point toward an unexpected mechanism(s) through which amyloid beta peptides contribute to AD pathogenesis. Specifically, we demonstrated that long but not short amyloid beta peptides act as competitive inhibitors of gamma-secretase, and thus lead to failed processing of multiple substrates and consequent dysregulation of multiple cell-signaling cascades. In addition, we determined that peptides generated from APP via a nonamyloidogenic pathway possess much less inhibitory potency. These discoveries, defining the most pathogenic products of the gamma-secretase-mediated proteolysis and pointing toward the cell-signaling pathways impaired in the disease, define promising targets for the novel AD therapeutics.
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.