Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease.
Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease.
复制标题
抑制 δ 分泌酶可改善阿尔茨海默病小鼠模型的认知功能
DOI：
10.1038/ncomms14740
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发表时间：
2017-03-27
影响因子：
16.6
通讯作者：
Ye K
中科院分区：
文献类型：
--
作者：
Zhang Z;Obianyo O;Dall E;Du Y;Fu H;Liu X;Kang SS;Song M;Yu SP;Cabrele C;Schubert M;Li X;Wang JZ;Brandstetter H;Ye K
δ-分泌酶，也称为天冬酰胺内肽酶 (AEP) 或 Legumain，是一种溶酶体半胱氨酸蛋白酶，可裂解淀粉样前体蛋白 (APP) 和 tau，介导阿尔茨海默病 (AD) 中的淀粉样蛋白 -β 和 tau 病理学。在这里，我们报告了口服生物活性且脑可渗透的 δ-分泌酶抑制剂在 AD 小鼠模型中的治疗效果。我们进行了高通量筛选，并鉴定出一种无毒且选择性的 δ-分泌酶抑制剂，称为化合物 11，它特异性阻断 δ-分泌酶，但不阻断其他相关的半胱氨酸蛋白酶。共晶结构分析揭示了此类化合物的双重活性位点定向和变构抑制模式。用这种抑制剂对 tau P301S 和 5XFAD 转基因小鼠进行长期治疗可减少 tau 和 APP 裂解，改善突触损失并增强长时程增强，从而保护记忆。因此，这些发现表明这种δ-分泌酶抑制剂可能是治疗AD的有效临床药物。 Delta 分泌酶可裂解淀粉样前体蛋白和 tau 蛋白，因此与阿尔茨海默病 (AD) 相关。作者在此开发了一系列口服生物活性小分子 δ 分泌酶抑制剂，并报告了其在 AD 小鼠模型中的治疗效果。
δ-secretase, also known as asparagine endopeptidase (AEP) or legumain, is a lysosomal cysteine protease that cleaves both amyloid precursor protein (APP) and tau, mediating the amyloid-β and tau pathology in Alzheimer's disease (AD). Here we report the therapeutic effect of an orally bioactive and brain permeable δ-secretase inhibitor in mouse models of AD. We performed a high-throughput screen and identified a non-toxic and selective δ-secretase inhibitor, termed compound 11, that specifically blocks δ-secretase but not other related cysteine proteases. Co-crystal structure analysis revealed a dual active site-directed and allosteric inhibition mode of this compound class. Chronic treatment of tau P301S and 5XFAD transgenic mice with this inhibitor reduces tau and APP cleavage, ameliorates synapse loss and augments long-term potentiation, resulting in protection of memory. Therefore, these findings demonstrate that this δ-secretase inhibitor may be an effective clinical therapeutic agent towards AD. Delta-secretases are associated with Alzheimer's disease (AD) as they cleave both amyloid precursor protein and tau. Here the authors develop a series of orally bioactive small molecule delta-secretase inhibitors and report its therapeutic effects in mouse models of AD.