Receptor tyrosine kinases positively regulate BACE activity and Amyloid-beta production through enhancing BACE internalization.
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.
Zou
Lin
L
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Wang
Zhu
Z
Shen
Li
L
Bao
Guo Bin
GB
Wang
Tian
T
Kang
Jiu Hong
JH
Pei
Gang
G
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
D016229:Amyloid beta-Peptides; D020800:Receptor, Nerve Growth Factor; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D053829:Amyloid Precursor Protein Secretases