Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer’s disease-related pathogenesis

Jin Cui; Xiaoyin Wang; Xiaohang Li; Xin Wang; Chenlu Zhang; Wei Li; Yangming Zhang; Haifeng Gu; Xin Xie; Fajun Nan; Jian Zhao; Gang Pei

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Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer’s disease-related pathogenesis

机译：靶向γ-/β-分泌酶相互作用可减少β-淀粉样蛋白的产生并改善阿尔茨海默氏病相关疾病的发病机理

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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.

机译：尽管数十年来在全球范围内做出了巨大的努力，但尚未出现用于治疗阿尔茨海默氏病的可缓解疾病的药物。靶向γ-分泌酶或β-位APP裂解酶1（BACE1）催化活性的分子被不良副作用所困扰。我们假设阻止BACE1和γ-分泌酶亚单位presenilin-1（PS1）之间的相互作用可能提供选择性抑制Aβ生成的替代策略。通过高通量筛选，我们发现3-α-酮酸（3AA）干扰PS1 / BACE1相互作用并减少Aβ的产生。系统合成了3AA的结构类似物，并鉴定了功能类似物XYT472B。光活化交联和生化竞争分析表明3AA和XYT472B与PS1结合，干扰PS1 / BACE1相互作用，并减少Aβ生成，而保留了分泌酶活性。此外，用XYT472B治疗APP / PS1小鼠可减轻认知功能障碍和Aβ相关病理。总之，我们的结果表明PS1 / BACE1相互作用的化学干扰是阿尔茨海默氏病治疗方法的一种有前途的策略。

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《Cell discovery.》 |2015年第7期|共页
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Jin Cui; Xiaoyin Wang; Xiaohang Li; Xin Wang; Chenlu Zhang; Wei Li; Yangming Zhang; Haifeng Gu; Xin Xie; Fajun Nan; Jian Zhao; Gang Pei;
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1. Amyloid-β protein (Aβ) Glu11 is the major β-secretase site of β-site amyloid-β precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis [J] . DengY., WangZ., WangR., The European Journal of Neuroscience . 2013,第11a12期

机译：淀粉样β蛋白（Aβ）Glu11是β位淀粉样β前体蛋白裂解酶1（BACE1）的主要β分泌酶位点，并且将裂解位点转移至AβAsp1有助于阿尔茨海默病的发病
2. Results of Beta Secretase-Inhibitor Clinical Trials Support Amyloid Precursor Protein-Independent Generation of Beta Amyloid in Sporadic Alzheimer’s Disease [J] . Vladimir Volloch, Sophia Rits Medical Sciences . 2018,第2期

机译：Beta分泌酶抑制剂临床试验的结果支持散发性阿尔茨海默氏病中淀粉样前体蛋白非依赖性的β淀粉样蛋白生成
3. Do proteomics analyses provide insights into reduced oxidative stress in the brain of an Alzheimer disease transgenic mouse model with an M631L amyloid precursor protein substitution and thereby the importance of amyloid-beta-resident methionine 35 in Alzheimer disease pathogenesis? [J] . SultanaR., RobinsonR.A.S., BaderLangeM., Antioxidants and redox signalling . 2012,第11期

机译：蛋白质组学分析是否可提供有关M631L淀粉样蛋白前体蛋白替代的阿尔茨海默氏病转基因小鼠模型脑部氧化应激降低的见解，以及淀粉样蛋白-β-蛋氨酸35在阿尔茨海默氏病发病机理中的重要性？
4. The "O-Acyl Isopeptide Method" for the Synthesis of Alzheimer's Disease-Related Amyloid beta Peptide (Abeta) 1-42 [C] . Youhei Sohma, Maiko Kimura, Yousuke Chiyomori American Peptide Symposium . 2006

机译：用于合成阿尔茨海默病相关淀粉样蛋白β肽（ABETA）1-42的“O-酰基异肽法”
5. Amyloid beta generation: Towards understanding the role of Pen-2 in the gamma-secretase complex, and, A comparison of amyloid fibrillogenesis using the novel fluorescent compound K114. [D] . Crystal, Adam S. 2005

机译：淀粉样蛋白β生成：试图了解Pen-2在γ-分泌酶复合物中的作用，以及使用新型荧光化合物K114比较淀粉样蛋白原纤维形成。
6. Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer’s disease-related pathogenesis [O] . Jin Cui, Xiaoyin Wang, Xiaohang Li, 2015

机译：靶向γ-/β-分泌酶相互作用可减少β-淀粉样蛋白的产生并改善阿尔茨海默氏病相关疾病的发病机理
7. Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer’s disease-related pathogenesis [O] . Jin Cui, Xiaoyin Wang, Xiaohang Li, 2015

机译：靶向γ-/β-分泌酶相互作用可减少β-淀粉样蛋白和改善阿尔茨海默病相关的发病机制

Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer’s disease-related pathogenesis

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