摘要
背景:β-分泌酶(BACE1)是与阿尔茨海默病(AD)发病机制有关的I型跨膜蛋白。由BACE1引发的淀粉状蛋白前体蛋白(APP)的切割和随后的γ-分泌酶会导致毒性Aβ肽的形成。与年龄匹配的健康对照组相比,在AD患者的CSF中检测到BACE1的水平升高,表明神经变性病症诱导BACE1的脱落。 目的:为了模拟这样的条件,我们检查血清剥夺是否刺激BACE1的蛋白水解依赖性分泌。 方法:使用western印迹分析检测在血清剥夺条件下培养的BACE1过表达细胞或ADAM10 / ADAM17敲除成纤维细胞中BACE1分泌。 结果:我们发现U251神经母细胞瘤或过表达BACE1的HEK293T细胞的血清剥夺刺激BACE1的分泌。使用ADAM10 / ADAM17敲除成纤维细胞和ADAM10和ADAM17的抑制剂,我们获得的数据显示这些蛋白酶参与血清饥饿诱导BACE1脱落的数据。这是未预料到,因为BACE1主要位于脂筏,而ADAM10主要位于非脂筏域中。我们假设血清剥夺导致膜的脂质组成的改变,其可以改变ADAM10和BACE1的定位。在此基础上,我们获得的结果表明提取膜胆固醇与甲基β环糊精孵育加强血清剥夺的影响,还发现分泌的BACE1对免疫沉淀的全长APP具有酶活性。 结论:血清饥饿诱导ADAM10介导的BACE1分泌。
关键词: 阿尔兹海默症、BACE1、ADAM10、ADAM17、胆固醇、蛋白质水解、脱落、分泌、血清饥饿
Current Alzheimer Research
Title:Serum Starvation Induces BACE1 Processing and Secretion
Volume: 14 Issue: 4
关键词: 阿尔兹海默症、BACE1、ADAM10、ADAM17、胆固醇、蛋白质水解、脱落、分泌、血清饥饿
摘要: Background: β-secretase (BACE1) is a type 1 transmembrane protein implicated in Alzheimer’s Disease (AD) pathogenesis. Cleavage of Amyloid Precursor Protein (APP), initiated by BACE1 and followed by γ-secretase, leads to the formation of toxic Aβ peptides. Increased levels of BACE1 have been detected in the CSF of AD patients compared to age-matched healthy controls indicating that neurodegenerative conditions induce shedding of BACE1.
Objective: To mimic such conditions, we examined whether serum deprivation stimulates proteolysis-dependent secretion of BACE1. Method: Detection of BACE1 secretion in BACE1 overexpressing cells or ADAM10/ADAM17 knockout fibroblasts cultured under serum deprivation conditions, using western blot analysis. Results: We found that serum deprivation of U251 neuroblastoma or HEK293T cells overexpressing BACE1 stimulated secretion of BACE1. Using ADAM10/ADAM17 knockout fibroblasts and inhibitors of both ADAM10 and ADAM17, we obtained data indicating that these proteases are involved in serum-starvation induced shedding of BACE1. This is unexpected since BACE1 is localized mainly in lipid rafts while ADAM10 is localized mainly in nonlipid raft domains. We hypothesized that serum deprivation results in alterations in the lipid composition of the membrane which can alter the localization of ADAM10 and BACE1. In support, we obtained results indicating that extraction of membrane cholesterol following incubation with methyl β cyclodextrin potentiated the effect of serum deprivation. Secreted BACE1 was also found to be enzymatically active towards immunoprecipiated full length APP. Conclusion: Serum starvation induces ADAM10-mediated BACE1 secretion.Export Options
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Cite this article as:
Serum Starvation Induces BACE1 Processing and Secretion, Current Alzheimer Research 2017; 14 (4) . https://dx.doi.org/10.2174/1567205013666161026091530
DOI https://dx.doi.org/10.2174/1567205013666161026091530 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
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