title: Cystatin C Shifts APP Processing from Amyloid-β Production towards Non-Amyloidgenic Pathway in Brain Endothelial Cells.
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.
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang 110122, China.
authors.forename: Xia-Fei
authors.initials: XF
authors.lastname: Wang
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang 110122, China.
authors.forename: Dong-Xin
authors.initials: DX
authors.lastname: Liu
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang 110122, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang 110122, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Xing
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang 110122, China.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Zhao
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang 110122, China.
authors.forename: Xiao-Xue
authors.initials: XX
authors.lastname: Qin
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang 110122, China.
authors.forename: De-Shu
authors.initials: DS
authors.lastname: Shang
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang 110122, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang 110122, China.
authors.forename: Wen-Gang
authors.initials: WG
authors.lastname: Fang
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang 110122, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang 110122, China.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Zhao
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang 110122, China.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Chen
mesh_terms: D000072197:ADAM10 Protein / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D055316:Cystatin C / Q000378:metabolism* / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D010446:Peptide Fragments / Q000096:biosynthesis*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020011:Protective Agents / Q000378:metabolism / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D055316:Cystatin C; D015853:Cysteine Proteinase Inhibitors; D008565:Membrane Proteins; D010446:Peptide Fragments; D020011:Protective Agents; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D046988:Proteasome Endopeptidase Complex; C447939:SIRT1 protein, human; D056564:Sirtuin 1