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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein
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Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein

机译：细胞pr病毒蛋白调节阿尔茨海默氏症淀粉样蛋白前体蛋白的β-分泌酶裂解

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摘要

Proteolytic processing of the amyloid precursor protein (APP) by β-secretase, β-site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid β (Aβ) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (PrP~C), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, remains enigmatic. Because both APP and PrP~C are subject to proteolytic processing by the same zinc metal-loproteases, we tested the involvement of PrP~C in the proteolytic processing of APP. Cellular overexpression of PrP~C inhibited the β-secretase cleavage of APP and reduced Aβ formation. Conversely, depletion of PrP~C in mouse N2a cells by siRNA led to an increase in Aβ peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapie-infected mice, Aβ levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the β-secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of PrP~C on the β-secretase cleavage of APP required the localization of PrP~C to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of PrP~C via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic Aβ is regulated by PrP~C and may have implications for both Alzheimer's and prion diseases.
机译：β-分泌酶（β位APP裂解酶）（BACE1）对淀粉样前体蛋白（APP）进行蛋白水解加工是生产淀粉样β（Aβ）肽的第一步，该过程涉及阿尔茨海默氏病的发病机理。 ion病毒蛋白（PrP〜C）的正常细胞功能仍然是令人困惑的，,病毒蛋白是可传播的海绵状脑病（例如克雅氏病）的病原体。因为APP和PrP〜C都受到相同的锌金属蛋白酶的蛋白水解加工，所以我们测试了PrP〜C在APP的蛋白水解加工中的参与。细胞中PrP〜C的过表达抑制APP的β-分泌酶裂解并减少Aβ的形成。相反，siRNA耗竭小鼠N2a细胞中的PrP〜C导致分泌到培养基中的Aβ肽增加。在PrP基因敲除小鼠的大脑中以及在两种被瘙痒病感染的小鼠的大脑中，Aβ含量均显着升高。与家族性人类病毒病相关的PrP的两个突变体PG14和A116V无法抑制APP的β-分泌酶裂解。使用PrP的构建体，我们表明PrP〜C对APP的β-分泌酶裂解的这种调节作用需要将PrP〜C定位于富含胆固醇的脂筏，并且是由PrP〜C的N末端多元区域介导的通过与糖胺聚糖的相互作用。总之，这是一种神经毒性Aβ的细胞产生受PrP〜C调节的机制，可能对阿尔茨海默氏病和病毒疾病都有影响。

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