Department of Molecular Life Sciences, Graduate School of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
Faculty of Pharma-Science, Teikyo University, Tokyo, Japan.
Commun Biol. 2023 Apr 8;6(1):383. doi: 10.1038/s42003-023-04771-9.
Inhibition of amyloid-β peptide (Aβ) accumulation in the brain is a promising approach for treatment of Alzheimer's disease (AD). Aβ is produced by β-secretase and γ-secretase in endosomes via sequential proteolysis of amyloid precursor protein (APP). Aβ and APP have a common feature to readily cluster to form multimers. Here, using multivalent peptide library screens, we identified a tetravalent peptide, LME-tet, which binds APP and Aβ via multivalent interactions. In cells, LME-tet-bound APP in the plasma membrane is transported to endosomes, blocking Aβ production through specific inhibition of β-cleavage, but not γ-cleavage. LME-tet further suppresses Aβ aggregation by blocking formation of the β-sheet conformation. Inhibitory effects are not observed with a monomeric peptide, emphasizing the significance of multivalent interactions for mediating these activities. Critically, LME-tet efficiently reduces Aβ levels in the brain of AD model mice, suggesting it may hold promise for treatment of AD.
抑制大脑中的淀粉样β肽（Aβ）积累是治疗阿尔茨海默病（AD）的一种有前途的方法。Aβ是通过β-分泌酶和γ-分泌酶在内体中通过淀粉样前体蛋白（APP）的顺序蛋白水解产生的。Aβ和 APP 具有易于聚集形成多聚体的共同特征。在这里，我们使用多价肽文库筛选，鉴定出一种四价肽 LME-tet，它通过多价相互作用与 APP 和 Aβ结合。在细胞中，LME-tet 结合的质膜上的 APP 被转运到内体中，通过特异性抑制β-裂解而不是γ-裂解来阻断 Aβ的产生。LME-tet 进一步通过阻止β-折叠构象的形成来抑制 Aβ聚集。单体肽没有观察到抑制作用，这强调了多价相互作用在介导这些活性中的重要性。至关重要的是，LME-tet 可有效降低 AD 模型小鼠大脑中的 Aβ水平，表明其可能有希望用于治疗 AD。
