Phosphorylation of amyloid precursor protein (APP) at Tyr687 regulates APP processing by alpha- and gamma-secretase |
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Authors: | Takahashi Keita Niidome Tetsuhiro Akaike Akinori Kihara Takeshi Sugimoto Hachiro |
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Affiliation: | a Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto University, Kyoto 606-8501, Japan b Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan |
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Abstract: | Abnormal proteolytic processing of amyloid precursor protein (APP) is a pathologic feature of Alzheimer’s disease. Recent studies have demonstrated that serine/threonine phosphorylation specifically at amino-acid residue Thr668 (APP695 numbering) regulates APP processing. In this study, we investigated the possibility that tyrosine phosphorylation of APP regulates APP processing. A tyrosine kinase inhibitor decreased expression of the C83 fragment which is a cleaved product of APP by α-secretase. By overexpressing APP mutant proteins, Tyr687 was found to be the major tyrosine kinase phosphorylation site. Expression of the C83 fragment was decreased in APPY687A-expressing cells relative to APP wild-type (APPWT)-expressing cells, which likely reflects the different cellular localization patterns of these two proteins. Expression of APP intracellular domain (AICD) which is a cleaved product of the C83 fragment by γ-secretase was decreased in C83Y687A-expressing cells. These results suggest that phosphorylation of APP at Tyr687 regulates APP processing by α- and γ-secretases, determining the expression level of AICD. |
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Keywords: | Alzheimer&rsquo s disease Amyloid precursor protein APP processing Phosphorylation Tyrosine 687 |
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