1. ¹Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
2. ²Clinical Molecular Medical Center, Children's Hospital, Chongqing University of Medical Sicences, Chongqing 400011, China
3. ³Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China

Correspondence: Gang Pei, Tel: 86-21-5492-1371; Fax: 86-21-5492-1011; E-mail: gpei@sibs.ac.cn

^*These authors contributed equally to this work

Received 16 December 2006; Revised 15 January 2007; Accepted 16 January 2007.

Abstract

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