Targeting the ?-/?-secretase interaction reduces ?-amyloid generation and ameliorates Alzheimer's disease-related pathogenesis.

ABSTRACT: Despite decades of intense global effort, no disease-modifying drugs for Alzheimer's disease have emerged. Molecules targeting catalytic activities of ?-secretase or ?-site APP-cleaving enzyme 1 (BACE1) have been beset by undesired side effects. We hypothesized that blocking the interaction between BACE1 and ?-secretase subunit presenilin-1 (PS1) might offer an alternative strategy to selectively suppress A? generation. Through high-throughput screening, we discovered that 3-?-akebonoic acid (3AA) interferes with PS1/BACE1 interaction and reduces A? production. Structural analogs of 3AA were systematically synthesized and the functional analog XYT472B was identified. Photo-activated crosslinking and biochemical competition assays showed that 3AA and XYT472B bind to PS1, interfere with PS1/BACE1 interaction, and reduce A? production, whereas sparing secretase activities. Furthermore, treatment of APP/PS1 mice with XYT472B alleviated cognitive dysfunction and A?-related pathology. Together, our results indicate that chemical interference of PS1/BACE1 interaction is a promising strategy for Alzheimer's disease therapeutics.

SUBMITTER: Cui J 

PROVIDER: S-EPMC4860824 | biostudies-other | 2015

REPOSITORIES: biostudies-other