The amyloid cascade hypothesis: are we poised for success or failure?
The amyloid cascade hypothesis: are we poised for success or failure?
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DOI：
10.1111/jnc.13632
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发表时间：
2016-10-01
影响因子：
4.7
通讯作者：
De Strooper, Bart
中科院分区：
文献类型：
--
作者：
Karran, Eric;De Strooper, Bart
Alois Alzheimer在1907年首次描述了阿尔茨海默病（AD）（Allgemeine Zeitschrift fur Psyciatrie und Psychisch-Gerichtliche Medizin 64，3，1907），尽管其他当代医生对AD脑中存在的神经病理学变化进行了类似的、相当完整的评估（Fischer，Monatsschr Psychiat Neurol 22，17，1907）。我们对AD的了解急剧增加，并继续加速。今年是一系列论文发表25年后，这些论文以各种方式阐述了AD的淀粉样蛋白级联假说（ACH（Beyreuther和Masters，Brain Pathol 1，241-251，1991;哈代和Allsop，Trends Pharmacol Sci 12，383-388，1991; Selkoe，Neuron 6，487-498，1991;哈代和希金斯，科学256，184-185，1992）。这篇综述将涵盖一些熟悉的领域，但我们也将ACH置于更广泛的背景下，将其与AD的其他假设进行比较，探索假设的演变以涵盖新的发现，并确定，无论假设本身的优点如何，它是否对学术界和工业界的研究领域有用。最后，我们将回顾ACH如何导致许多治疗方法，迄今为止，所有这些方法都未能在临床试验中达到其主要疗效终点，并反思未来可能会发生什么。
The first description of Alzheimer's disease (AD) was made in 1907 by Alois Alzheimer (Allgemeine Zeitschrift fur Psyciatrie und Psychisch-Gerichtliche Medizin 64, 3, 1907), although other contemporary physicians had made similar, and rather more complete, assessments of the neuropathological changes present in the AD brain (Fischer, Monatsschr Psychiat Neurol 22, 17, 1907). Our knowledge of AD has increased dramatically and continues to accelerate. This year is 25years after the publication of a series of papers that, in various ways, articulated the amyloid cascade hypothesis (ACH) for AD (Beyreuther and Masters, Brain Pathol 1, 241-251, 1991; Hardy and Allsop, Trends Pharmacol Sci 12, 383-388, 1991; Selkoe, Neuron 6, 487-498, 1991; Hardy and Higgins, Science 256, 184-185, 1992). This review will cover some familiar territory, but we shall also place the ACH into a wider context, compare it with other hypotheses for AD, explore the evolution of the hypothesis to encompass new findings, and determine, irrespective of the merits of the hypothesis itself, whether it has been useful for the research field, both in academia and in industry. Finally, we shall review how the ACH has led to a number of therapeutic approaches, all of which have, to date, failed to reach their primary efficacy end-points in clinical trials and reflect upon what the future may hold.