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Cystatin C Shifts APP Processing from Amyloid-β Production towards Non-Amyloidgenic Pathway in Brain Endothelial Cells
- Source :
- PLoS ONE, Vol 11, Iss 8, p e0161093 (2016), PLoS ONE
- Publication Year :
- 2016
- Publisher :
- Public Library of Science (PLoS), 2016.
-
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.
- Subjects :
- 0301 basic medicine
Physiology
ADAM10
lcsh:Medicine
Biochemistry
Epithelium
ADAM10 Protein
Amyloid beta-Protein Precursor
Mathematical and Statistical Techniques
Ubiquitin
Sirtuin 1
Animal Cells
Medicine and Health Sciences
Aspartic Acid Endopeptidases
Small interfering RNAs
Senile plaques
Enzyme-Linked Immunoassays
lcsh:Science
Cells, Cultured
Multidisciplinary
biology
Brain
Neurodegenerative Diseases
Cysteine protease
Cell biology
Up-Regulation
Precipitation Techniques
Nucleic acids
Protein Transport
Neurology
Cell Processes
Physical Sciences
Cellular Types
Anatomy
Metabolic Networks and Pathways
Statistics (Mathematics)
Research Article
Proteasome Endopeptidase Complex
Down-Regulation
Cysteine Proteinase Inhibitors
Protective Agents
Research and Analysis Methods
03 medical and health sciences
Downregulation and upregulation
Alzheimer Disease
Mental Health and Psychiatry
mental disorders
Genetics
Humans
Immunoprecipitation
Secretion
RNA, Messenger
Cystatin C
Statistical Methods
Non-coding RNA
Immunoassays
Analysis of Variance
Amyloid beta-Peptides
lcsh:R
Endothelial Cells
Membrane Proteins
Biology and Life Sciences
Protein Secretion
Proteins
Epithelial Cells
Cell Biology
Peptide Fragments
Gene regulation
030104 developmental biology
Biological Tissue
biology.protein
Immunologic Techniques
RNA
Dementia
lcsh:Q
Gene expression
Amyloid Precursor Protein Secretases
Physiological Processes
Amyloid precursor protein secretase
Protein Processing, Post-Translational
Mathematics
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 11
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....87298c2dfe4f7144b85d24dd51606b18