title: Receptor tyrosine kinases positively regulate BACE activity and Amyloid-beta production through enhancing BACE internalization.
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.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zou
authors.forename: Zhu
authors.initials: Z
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Guo Bin
authors.initials: GB
authors.lastname: Bao
authors.forename: Tian
authors.initials: T
authors.lastname: Wang
authors.forename: Jiu Hong
authors.initials: JH
authors.lastname: Kang
authors.forename: Gang
authors.initials: G
authors.lastname: Pei
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D066246:ErbB Receptors / Q000502:physiology; D016391:Genes, src / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D020800:Receptor, Nerve Growth Factor / Q000502:physiology; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D020800:Receptor, Nerve Growth Factor; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D053829:Amyloid Precursor Protein Secretases