Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer's disease-related pathogenesis.
Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer's disease-related pathogenesis.
复制标题
针对γ-/β-分泌酶相互作用可减少β-淀粉样蛋白的生成并改善阿尔茨海默病相关的发病机制。
DOI：
10.1038/celldisc.2015.21
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发表时间：
2015
期刊：
影响因子：
33.5
通讯作者：
Pei G
中科院分区：
文献类型：
--
作者：
Cui J;Wang X;Li X;Wang X;Zhang C;Li W;Zhang Y;Gu H;Xie X;Nan F;Zhao J;Pei G
尽管经过数十年的全球努力，但还没有出现针对阿尔茨海默病的疾病修饰药物。靶向γ-分泌酶或β-位点APP-裂解酶1（BACE 1）的催化活性的分子已经受到不期望的副作用的困扰。我们假设阻断BACE 1和γ-分泌酶亚基早老素-1（PS1）之间的相互作用可能提供一种选择性抑制Aβ生成的替代策略。通过高通量筛选，我们发现3-α-酮酸（3AA）能够干扰PS1/BACE 1的相互作用，减少Aβ的产生。系统地合成了3AA的结构类似物，并鉴定了功能类似物XYT 472 B。光活化交联和生化竞争实验表明，3AA和XYT 472 B与PS1结合，干扰PS1/BACE 1相互作用，减少Aβ的产生，但不影响分泌酶活性。此外，用XYT 472 B治疗APP/PS1小鼠减轻了认知功能障碍和Aβ相关病理。总之，我们的结果表明，PS1/BACE 1相互作用的化学干扰是阿尔茨海默病治疗的一种有前途的策略。
Despite decades of intense global effort, no disease-modifying drugs for Alzheimer’s disease have emerged. Molecules targeting catalytic activities of γ-secretase or β-site APP-cleaving enzyme 1 (BACE1) have been beset by undesired side effects. We hypothesized that blocking the interaction between BACE1 and γ-secretase subunit presenilin-1 (PS1) might offer an alternative strategy to selectively suppress Aβ generation. Through high-throughput screening, we discovered that 3-α-akebonoic acid (3AA) interferes with PS1/BACE1 interaction and reduces Aβ production. Structural analogs of 3AA were systematically synthesized and the functional analog XYT472B was identified. Photo-activated crosslinking and biochemical competition assays showed that 3AA and XYT472B bind to PS1, interfere with PS1/BACE1 interaction, and reduce Aβ production, whereas sparing secretase activities. Furthermore, treatment of APP/PS1 mice with XYT472B alleviated cognitive dysfunction and Aβ-related pathology. Together, our results indicate that chemical interference of PS1/BACE1 interaction is a promising strategy for Alzheimer’s disease therapeutics.