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首页> 外文期刊>Biochemistry >Cleavage of Alzheimer's amyloid precursor protein by alpha-secretase occurs at the surface of neuronal cells.
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Cleavage of Alzheimer's amyloid precursor protein by alpha-secretase occurs at the surface of neuronal cells.

机译：α-分泌酶切割阿尔茨海默氏症淀粉样蛋白前体蛋白发生在神经元细胞表面。

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摘要

The amyloid precursor protein (APP) is proteolytically processed predominantly by alpha-secretase to release the ectodomain (sAPPalpha). In this study, we have addressed the cellular location of the constitutive alpha-secretase cleavage of endogenous APP in a neuronal cell line. Incubation of the neuroblastoma cell line IMR32 at 20 degrees C prevented the secretion into the medium of soluble wild-type APP cleaved by alpha-secretase as revealed by both immunoelectrophoretic blot analysis with a site-specific antibody and immunoprecipitation following metabolic labeling of the cells. No sAPPalpha was detected in the cell lysates following incubation of the cells at 20 degrees C, indicating that alpha-secretase does not cleave APP in the secretory pathway prior to or within the trans-Golgi network. Parallel studies using an antibody that recognizes specifically the neoepitope revealed on soluble APP cleaved by beta-secretase indicated that this enzyme was acting intracellularly. alpha-Secretase is a zinc metalloproteinase susceptible to inhibition by hydroxamate-based compounds such as batimastat [Parvathy, S., et al. (1998) Biochemistry 37, 1680-1685]. Incubation of the cells with a cell-impermeant, biotinylated hydroxamate inhibitor inhibited the release of sAPPalpha by >92%, indicating that alpha-secretase is cleaving APP almost exclusively at the cell surface. The observation that alpha-secretase cleaves APP at the cell surface, while beta-secretase can act earlier in the secretory pathway within the neuronal cell line indicates that there must be strict control mechanisms in place to ensure that APP is normally cleaved primarily by alpha-secretase in the nonamyloidogenic pathway to produce the neuroprotective sAPPalpha.
机译：淀粉样蛋白前体蛋白（APP）主要通过alpha分泌酶进行蛋白水解处理，以释放胞外域（sAPPalpha）。在这项研究中，我们已经解决了神经元细胞系中内源性APP的本构性α分泌酶裂解的细胞位置。神经母细胞瘤细胞系IMR32在20°C的孵育可防止分泌分泌经α-分泌酶切割的可溶性野生型APP，如通过位点特异性抗体的免疫电泳分析和细胞代谢标记后的免疫沉淀所揭示的那样。在20°C孵育细胞后，在细胞裂解物中未检测到sAPPalpha，这表明在反式高尔基网络之前或之内，α-分泌酶不会在分泌途径中切割APP。使用特异性识别新表位的抗体进行的平行研究表明，该蛋白在被β-分泌酶切割的可溶性APP上显示出这种酶在细胞内的作用。 α-分泌酶是一种锌金属蛋白酶，易于被基于异羟肟酸酯的化合物如巴马司他抑制[Parvathy，S.，et al。 （1998）Biochemistry 37，1680-1685]。用不渗透细胞的生物素化异羟肟酸酯抑制剂孵育细胞可抑制sAPPalpha的释放> 92％，这表明α-分泌酶几乎只在细胞表面切割APP。 α-分泌酶可在细胞表面切割APP的观察结果，而β-分泌酶可在神经元细胞系内的分泌途径中更早发挥作用，这表明必须建立严格的控制机制，以确保APP通常主要被α-分泌酶切割。非淀粉样蛋白生成途径中的β-内分泌酶产生神经保护性sAPPalpha。

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