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.
Highlights
Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly population
To evaluate the effect of cystatin C (CysC) on amyloid protein precursor (APP) processing in human brain microvascular endothelial cells (HBMEC), the concentrations of Aβ40 and soluble amyloid protein precursor α (sAPPα) in the culture medium of HBMEC was measured by Enzyme-Linked Immunosorbent Assay (ELISA)
The results showed that CysC reduced the levels of Aβ40 in the culture medium of HBMEC in a time-dependent manner, with the decrease reaching statistical difference at 8 hr and 12 hr after CysC application (Fig 1A)
Summary
Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly population. Progressive accumulation of amyloid-β peptide (Aβ) in the brain parenchyma, caused by imbalance between Aβ production and clearance, is the primary mechanism driving AD pathogenesis [1]. In more than 80% of AD individuals, Aβ is deposited within cerebral vessel wall, termed as cerebral amyloid angiopathy (CAA) [2,3]. CAA was previously interpreted as the result of insufficient clearance of neuronal Aβ from brain parenchyma in AD because cerebrovascular system is the major pathway mediating brain Aβ elimination [4,5]. PLOS ONE | DOI:10.1371/journal.pone.0161093 August 17, 2016
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