Tse Kai-Hei, Herrup Karl
Division of Life Science and the State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
J Neurochem. 2017 Nov;143(4):432-444. doi: 10.1111/jnc.14079. Epub 2017 Jun 21.
Many have criticized the amyloid cascade hypothesis of Alzheimer's disease for its inconsistencies and failures to either accurately predict disease symptoms or guide the development of productive therapies. In addition to criticisms, however, we believe that the field would benefit from having alternative narratives and disease models that can either replace or function alongside of an amyloid-centric view of Alzheimer's. This review is an attempt to meet that need. We offer three experimentally verified amyloid-independent mechanisms, each of which plausibly contributes substantially to the aetiology of Alzheimer's disease: loss of DNA integrity, faulty cell cycle regulation, regression of myelination. We outline the ways in which the failure of each can contribute to AD initiation and progression, and review how, acting alone or in combination with each other, they are sufficient for explaining the full range of AD pathologies. Yet, these three alternatives represent only a few of the many non-amyloid mechanisms that can explain AD pathogenesis. Therefore instead of proposing a single 'alternative hypothesis' to the amyloid cascade theory, sporadic AD is pictured as the result of independent yet intersecting age-related pathologies that afflict the ageing human brain. This article is part of the series "Beyond Amyloid". Cover Image for this issue: doi. 10.1111/jnc.13823.
许多人批评阿尔茨海默病的淀粉样蛋白级联假说，因其存在不一致性，且未能准确预测疾病症状或指导有效疗法的开发。然而，除了批评之外，我们认为该领域将受益于拥有替代的叙述方式和疾病模型，这些模型可以取代以淀粉样蛋白为中心的阿尔茨海默病观点，或与之并行发挥作用。本综述旨在满足这一需求。我们提出了三种经实验验证的与淀粉样蛋白无关的机制，每一种机制都可能在很大程度上对阿尔茨海默病的病因学有显著贡献：DNA完整性丧失、细胞周期调控异常、髓鞘形成倒退。我们概述了每种机制的失灵可能导致阿尔茨海默病起始和进展的方式，并回顾了它们单独或相互结合时，如何足以解释阿尔茨海默病的全部病理表现。然而，这三种替代机制只是众多能够解释阿尔茨海默病发病机制的非淀粉样蛋白机制中的一部分。因此，散发性阿尔茨海默病并非被视为淀粉样蛋白级联理论的单一“替代假说”的结果，而是被描绘为影响衰老人类大脑的独立但相互交叉的与年龄相关的病理过程的结果。本文是“超越淀粉样蛋白”系列文章的一部分。本期封面图片：doi. 10.1111/jnc.13823。
