Open AccessCystatin C Shifts APP Processing from Amyloid-β Production towards Non-Amyloidgenic Pathway in Brain Endothelial Cells
Author(s) -
Xia-Fei Wang,
Dongxin Liu,
Yue Liang,
Lili Xing,
Wenhui Zhao,
Xiaoxue Qin,
De-Shu Shang,
Bo Li,
Wen-Gang Fang,
Liu Cao,
Weidong Zhao,
Yuhua Chen
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0161093
Subject(s) - adam10 , downregulation and upregulation , cystatin c , amyloid precursor protein , amyloid precursor protein secretase , alpha secretase , chemistry , secretion , proteasome , cystatin , microbiology and biotechnology , protein precursor , alzheimer's disease , biochemistry , medicine , biology , metalloproteinase , matrix metalloproteinase , disintegrin , disease , enzyme , renal function , gene
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.