Abstract:
:Amyloid-beta (Abeta) peptide, the primary constituent of senile plaques in Alzheimer's disease (AD), is generated by beta-secretase- and gamma-secretase-mediated sequential proteolysis of the amyloid precursor protein (APP). The aspartic protease, beta -site APP cleavage enzyme (BACE), has been identified as the main beta-secretase in brain but the regulation of its activity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Abeta 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 Abeta 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 Abeta production, indicating the requirement of BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity and Abeta 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 Abeta production.
journal_name
Cell Resjournal_title
Cell researchauthors
Zou L,Wang Z,Shen L,Bao GB,Wang T,Kang JH,Pei Gdoi
10.1038/cr.2007.5subject
Has Abstractpub_date
2007-05-01 00:00:00pages
389-401issue
5eissn
1001-0602issn
1748-7838pii
cr20075journal_volume
17pub_type
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