Nalivaeva Natalia N, Turner Anthony J
School of Biomedical Sciences, University of Leeds, Leeds, UK.
Laboratory of Physiology and Pathology of CNS, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS, St. Petersburg, Russia.
Br J Pharmacol. 2019 Sep;176(18):3447-3463. doi: 10.1111/bph.14593. Epub 2019 Mar 11.
Targeting the amyloid-β (Aβ) peptide cascade has been at the heart of therapeutic developments in Alzheimer's disease (AD) research for more than 25 years, yet no successful drugs have reached the marketplace based on this hypothesis. Nevertheless, the genetic and other evidence remains strong, if not overwhelming, that Aβ is central to the disease process. Most attention has focused on the biosynthesis of Aβ from its precursor protein through the successive actions of the β- and γ-secretases leading to the development of inhibitors of these membrane proteases. However, the levels of Aβ are maintained through a balance of its biosynthesis and clearance, which occurs both through further proteolysis by a family of amyloid-degrading enzymes (ADEs) and by a variety of transport processes. The development of late-onset AD appears to arise from a failure of these clearance mechanisms rather than by overproduction of the peptide. This review focuses on the nature of these clearance mechanisms, particularly the various proteases known to be involved, and their regulation and potential as therapeutic targets in AD drug development. The majority of the ADEs are zinc metalloproteases [e.g., the neprilysin (NEP) family, insulin-degrading enzyme, and angiotensin converting enzymes (ACE)]. Strategies for up-regulating the expression and activity of these enzymes, such as genetic, epigenetic, stem cell technology, and other pharmacological approaches, will be highlighted. Modifiable physiological mechanisms affecting the efficiency of Aβ clearance, including brain perfusion, obesity, diabetes, and sleep, will also be outlined. These new insights provide optimism for future therapeutic developments in AD research. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.
25多年来，针对淀粉样β（Aβ）肽级联反应一直是阿尔茨海默病（AD）研究治疗进展的核心，但基于这一假设，尚无成功的药物上市。然而，即使不是压倒性的，遗传和其他证据仍然有力地表明，Aβ是疾病进程的核心。大多数注意力都集中在Aβ从前体蛋白的生物合成上，这是通过β-和γ-分泌酶的连续作用实现的，从而导致了这些膜蛋白酶抑制剂的开发。然而，Aβ的水平是通过其生物合成和清除的平衡来维持的，清除过程既包括通过一类淀粉样降解酶（ADEs）的进一步蛋白水解，也包括通过各种转运过程。晚发性AD的发生似乎是由于这些清除机制的失效，而不是该肽的过量产生。本综述重点关注这些清除机制的本质，特别是已知参与其中的各种蛋白酶，以及它们在AD药物开发中的调节作用和作为治疗靶点的潜力。大多数ADEs是锌金属蛋白酶[例如，中性内肽酶（NEP）家族、胰岛素降解酶和血管紧张素转换酶（ACE）]。将重点介绍上调这些酶表达和活性的策略，如基因、表观遗传、干细胞技术和其他药理学方法。还将概述影响Aβ清除效率的可改变生理机制，包括脑灌注、肥胖、糖尿病和睡眠。这些新见解为AD研究的未来治疗进展带来了乐观情绪。相关文章：本文是关于痴呆症和阿尔茨海默病治疗：精准医学新方向主题部分的一部分。要查看本部分的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc。
