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Cystatin C Shifts APP Processing from Amyloid-β Production towards Non-Amyloidgenic Pathway in Brain Endothelial Cells

Author

Listed:
  • Xia-Fei Wang
  • Dong-Xin Liu
  • Yue Liang
  • Li-Li Xing
  • Wen-Hui Zhao
  • Xiao-Xue Qin
  • De-Shu Shang
  • Bo Li
  • Wen-Gang Fang
  • Liu Cao
  • Wei-Dong Zhao
  • Yu-Hua Chen

Abstract

Amyloid-β (Aβ), the major component of neuritic plaques in Alzheimer’s disease (AD), is derived from sequential proteolytic cleavage of amyloid protein precursor (APP) by secretases. In this study, we found that cystatin C (CysC), a natural cysteine protease inhibitor, is able to reduce Aβ40 secretion in human brain microvascular endothelial cells (HBMEC). The CysC-induced Aβ40 reduction was caused by degradation of β-secretase BACE1 through the ubiquitin/proteasome pathway. In contrast, we found that CysC promoted secretion of soluble APPα indicating the activated non-amyloidogenic processing of APP in HBMEC. Further results revealed that α-secretase ADAM10, which was transcriptionally upregulated in response to CysC, was required for the CysC-induced sAPPα secretion. Knockdown of SIRT1 abolished CysC-triggered ADAM10 upregulation and sAPPα production. Taken together, our results demonstrated that exogenously applied CysC can direct amyloidogenic APP processing to non-amyloidgenic pathway in brain endothelial cells, mediated by proteasomal degradation of BACE1 and SIRT1-mediated ADAM10 upregulation. Our study unveils previously unrecognized protective role of CysC in APP processing.

Suggested Citation

  • Xia-Fei Wang & Dong-Xin Liu & Yue Liang & Li-Li Xing & Wen-Hui Zhao & Xiao-Xue Qin & De-Shu Shang & Bo Li & Wen-Gang Fang & Liu Cao & Wei-Dong Zhao & Yu-Hua Chen, 2016. "Cystatin C Shifts APP Processing from Amyloid-β Production towards Non-Amyloidgenic Pathway in Brain Endothelial Cells," PLOS ONE, Public Library of Science, vol. 11(8), pages 1-16, August.
    • Handle: RePEc:plo:pone00:0161093
    DOI: 10.1371/journal.pone.0161093
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    1. Anna, Petrenko, . "Мaркування готової продукції як складова частина інформаційного забезпечення маркетингової діяльності підприємств овочепродуктового підкомплексу," Agricultural and Resource Economics: International Scientific E-Journal, Agricultural and Resource Economics: International Scientific E-Journal, vol. 2(01).
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