Novel Chemical Modulators for BACE1-Mediated Cleavage of Amyloid Beta Precursor Protein

2018

The beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is an enzyme that mediates the generation of amyloid beta peptide, a core component of amyloid plaque in Alzheimer’s disease. The current research is intended to understand how BACE1 is regulated in neurons in order to gain insights as to how to therapeutically control BACE1 activity. This regulation has implications for regulating amyloid beta generation in a safer and more effective manner. We discovered several compounds that contain a characteristic drug-like chemical core known as 8-hydroxyquinoline (8HQ). These compounds play a role in regulating the function of BACE1 in processing APP. Based on this observation, the current proposal will investigate the mechanism underlying the BACE1-regulating action of 8HQ, with the ultimate goal of evaluating this compound for its therapeutic potential as an AD drug candidate.

2017

The beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a promising drug target in Alzheimer’s disease (AD). BACE1 is a membrane-bound proteolytic enzyme that mediates the first step in producing the amyloid beta peptide. A number of genetic and pathophysiological studies have shown the essential role for BACE1 in AD. Despite its clinical importance, mechanisms regulating BACE1 functions in the brain are unknown and thus under intense investigation. We first developed an assay using neuronal cells that can monitor the proteolytic cleavage of APP by BACE1 by detection of the direct cleavage product sAPPbeta. Using this assay, we screened for small molecules and identified a number of chemical compounds that can suppress the BACE1-mediated cleavage of APP through previously unknown mechanisms (yet sparing the catalytic activity of BACE1). In this proposal, we will further validate the identified small molecules and use them as chemical tools to uncover new biological pathways regulating BACE1 in the brain. Given high relevance of BACE1 to AD pathogenesis, the successful completion of our proposed studies may yield new insight to help devise more efficacious and safe ways for controlling BACE1 activity for therapeutic means.