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

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

PLOS ONE, 2016, vol. 11, issue 8, 1-16

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.

Date: 2016
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0161093

DOI: 10.1371/journal.pone.0161093

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