Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

摘要

Amyloid-β (AP) peptide, the primary constituent of senile plaques in Alzheimer's disease (AD), is generated byβ-secretase- and γ-secretase-mediated sequential proteolysis of the amyloid precursor protein (APP). The aspartic pro-tease, β -site APP cleavage enzyme (BACE), has been identified as the main P-secretase in brain but the regulation of itsactivity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Aβ production are enhancedafter stimulation of receptor tyrosine kinases (RTKs), such as the receptors for epidermal growth factor (EGF) and nervegrowth factor (NGF), in cultured cells as well as in mouse hippocampus. Furthermore, stimulation of RTKs also inducesBACE internalization into endosomes and Golgi apparatus. This enhancement of BACE activity and Aβ production uponRTK activation could be specifically inhibited by Src family kinase inhibitors and by depletion of endogenous c-Src withRNAi, and could be mimicked by over-expressed c-Src. Moreover, blockage of BACE internalization by a dominantnegative form of Rab5 also abolished the enhancement of BACE activity and Aβ production, indicating the requirementof BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity andAβ production are under the regulation of RTKs and this is achieved via RTK-stimulated BACE internalization, andsuggests that an aberration of such regulation might contribute to pathogenic Aβ production.