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New protein kinase C activator regulates amyloid precursor protein processing in vitro by increasing α-secretase activity

Authors

  • Hong-Qi Yang,

    1. Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, P.R. China
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  • Jing Pan,

    1. Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, P.R. China
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  • Mao-Wen Ba,

    1. Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, P.R. China
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  • Zhi-Kun Sun,

    1. Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, P.R. China
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  • Guo-Zhao Ma,

    1. Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, P.R. China
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  • Guo-Qiang Lu,

    1. Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, P.R. China
    2. Laboratory of Neurodegenerative Diseases, Institute of Health Science, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai JiaoTong University School of Medicine, Shanghai 200025, P.R. China
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  • Qin Xiao,

    1. Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, P.R. China
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  • Sheng-Di Chen

    1. Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, P.R. China
    2. Laboratory of Neurodegenerative Diseases, Institute of Health Science, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai JiaoTong University School of Medicine, Shanghai 200025, P.R. China
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Dr Sheng-Di Chen, 1Department of Neurology and Institute of Neurology, as above.
E-mail: address: chen_sd@medmail.com.cn

Abstract

The beta amyloid (Aβ) cascade has been at the forefront of the hypothesis used to describe the pathogenesis of Alzheimer's disease (AD). It is generally accepted that drugs that can regulate the processing of the amyloid precursor protein (APP) toward the non-amyloidogenic pathway may have a therapeutic potential. Previous studies have shown that protein kinase C (PKC) hypofunction has an important role in AD pathophysiology. Therefore, the effects of a new PKC activator, α-APP modulator [(2S,5S)-(E,E)-8-(5-(4-(trifluoromethyl)phenyl)-2,4-pentadienoylamino)benzolactam (TPPB)], on APP processing were investigated. Using PC12 cells and SH-SY5YAPP695 cells, it was found that TPPB promoted the secretion of sAPPα without affecting full-length expression of APP. The increase in sAPPα by TPPB was blocked by inhibitors of PKC, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and tyrosine kinase, suggesting the involvement of these signal transduction pathways. TPPB increased α-secretase activity [a disintegrin and metalloproteinase (ADAM)10 and 17], as shown by direct fluorescence activity detection and Western blot analysis. TPPB-induced sAPPα release was blocked by the metalloproteinase inhibitor TAPI-2, furin inhibitor CMK and by the protein-trafficking inhibitor brefeldin. The results also showed that TPPB decreased β-secretase activity, Aβ40 release and beta site APP-cleaving enzyme 1 (BACE1) expression, but did not significantly affect neprilysin (NEP) and insulin-degrading enzyme (IDE) expression. Our data indicate that TPPB could direct APP processing towards the non-amyloidogenic pathway by increasing α-secretase activity, and suggest its therapeutic potential in AD.

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