Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Neurochem Res. 2019 Jun;44(6):1289-1296. doi: 10.1007/s11064-019-02756-x. Epub 2019 Feb 26.
The accumulation of amyloid beta (Aβ) in the brain is believed to play a central role in the development and progression of Alzheimer's disease. Revisions to the amyloid cascade hypothesis now acknowledge the dynamic equilibrium in which Aβ exists and the importance of enzymes involved in the production and breakdown of Aβ in maintaining healthy Aβ levels. However, while a wealth of pharmacological and immunological therapies are being generated to inhibit the Aβ-producing enzymes, β-site APP cleavage enzyme 1 and γ-secretase, the therapeutic potential of stimulating Aβ-degrading enzymes such as neprilysin, endothelin-converting enzyme-1 and insulin-degrading enzyme remains relatively unexplored. Recent evidence indicates that increasing Aβ degradation as opposed to inhibiting synthesis is a more effective strategy to prevent Aβ build-up. Therefore Aβ degrading enzymes have become valuable targets of therapy. In this review, we discuss the pathway of Aβ synthesis and clearance along with the opportunities they present for therapeutic intervention, the benefits of increasing the expression/activity of Aβ-degrading enzymes, and the untapped therapeutic potential of enzyme activation.
淀粉样蛋白β（Aβ）在大脑中的积累被认为在阿尔茨海默病的发展和进展中起核心作用。对淀粉样蛋白级联假说的修订现在承认了 Aβ 存在的动态平衡以及参与 Aβ 产生和分解的酶在维持健康的 Aβ 水平中的重要性。然而，尽管正在生成大量的药理学和免疫学疗法来抑制 Aβ 产生酶，即β-位点 APP 切割酶 1 和 γ-分泌酶，但刺激 Aβ 降解酶，如 Neprilysin、内皮素转换酶 1 和胰岛素降解酶的治疗潜力仍然相对未被探索。最近的证据表明，增加 Aβ 的降解而不是抑制合成是预防 Aβ 积累的更有效策略。因此，Aβ 降解酶已成为有价值的治疗靶点。在这篇综述中，我们讨论了 Aβ 合成和清除的途径以及它们为治疗干预提供的机会，增加 Aβ 降解酶的表达/活性的益处，以及酶激活的未开发的治疗潜力。
