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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inhibition of amyloid precursor protein processing by β-secretase through site-directed antibodies
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Inhibition of amyloid precursor protein processing by β-secretase through site-directed antibodies

机译：β-分泌酶通过定点抗体抑制淀粉样蛋白前体蛋白加工

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摘要

Amyloid-β peptide (AβP) that accumulates in the Alzheimer's diseased brain is derived from proteolytic processing of the amyloid precursor protein (APP) by means of β- and γ-secretases. The β-secretase APP cleaving enzyme (BACE), which generates the N terminus of AβP, has become a target of intense research aimed at blocking the enzyme activity, thus reducing AβP and, subsequently, plaque formation. The search for specific inhibitors of β-secretase activity as a possible treatment for Alzheimer's disease intensified with the discovery that BACE may be involved in processing other non-APP substrates. The presence of the APP-BACE complex in early endosomes highlights the cell surface as a potential therapeutic target, suggesting that interference in APP-BACE interaction at the cell surface may affect amyloid-β production. We present here a unique approach to inhibit AβP production by means of antibodies against the β-secretase cleavage site of APP. These antibodies were found to bind human APP overex-pressed by CHO cells, and the formed immunocomplex was visualized in the early endosomes. Indeed, blocking of the β-secretase site by these antibodies interfered with BACE activity and inhibited both intracellular and extracellular AβP formation in these cells.
机译：积累在阿尔茨海默氏病患病大脑中的淀粉样β肽（AβP）来源于淀粉样前体蛋白（APP）通过β和γ分泌酶的蛋白水解过程。产生AβPN末端的β-分泌酶APP裂解酶（BACE）已成为旨在阻止该酶活性从而减少AβP进而减少斑块形成的大量研究的目标。由于发现BACE可能参与其他非APP底物的加工，因此寻找特定的β-分泌酶活性抑制剂作为阿尔茨海默氏病的可能治疗方法的呼声越来越高。早期内体中APP-BACE复合物的存在突出了细胞表面作为潜在治疗靶点的可能性，这表明对细胞表面APP-BACE相互作用的干扰可能会影响淀粉样β的产生。我们在这里提出一种独特的方法，通过针对APP的β-分泌酶切割位点的抗体来抑制AβP的产生。发现这些抗体结合由CHO细胞过度表达的人APP，并且在早期的内体中可见形成的免疫复合物。实际上，这些抗体阻断β-分泌酶位点会干扰BACE活性，并抑制这些细胞中细胞内和细胞外AβP的形成。

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