Alzheimer's Disease
Alzheimer's Disease
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DOI：
10.1101/cshperspect.a004457
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发表时间：
2011-07-01
影响因子：
7.2
通讯作者：
Selkoe, Dennis J.
中科院分区：
文献类型：
--
作者：
Selkoe, Dennis J.
在过去的三十年里，生物化学病理学和人类遗传学的进展已经阐明了生物医学中最神秘的主题之一-神经退行性变。神经系统的命名疾病，如阿尔茨海默氏症、帕金森氏症和亨廷顿氏病，长期以来一直以机械论的无知为特征，在我们对其分子基础的理解方面取得了惊人的进展。这些疾病和相关疾病的一个中心主题是某些正常可溶的神经元蛋白质可以错误折叠和聚集成寡聚体和淀粉样纤维，这可以赋予深刻的细胞毒性。也许最重要的例子，无论是在其社会影响和多远的知识已经走向临床，是阿尔茨海默病（AD）。在这里，我们将回顾经典的蛋白质病变的障碍，提供了一个路线图的病因和发病机制。我们将讨论如何阐明阿尔茨海默病家族形式的基因型与表型的关系，突出了两种可溶性蛋白质，淀粉样β蛋白和tau蛋白的错误折叠和蛋白质稳态改变的重要性，这表明基于机制的治疗靶点已经导致临床试验。
Over the last three decades, advances in biochemical pathology and human genetics have illuminated one of the most enigmatic subjects in biomedicine-neurodegeneration. Eponymic diseases of the nervous system such as Alzheimer's, Parkinson's, and Huntington's diseases that were long characterized by mechanistic ignorance have yielded striking progress in our understanding of their molecular underpinnings. A central theme in these and related disorders is the concept that certain normally soluble neuronal proteins can misfold and aggregate into oligomers and amyloid fibrilswhich can confer profound cytotoxicity. Perhaps the foremost example, both in terms of its societal impact and how far knowledge has moved toward the clinic, is that of Alzheimer's disease (AD). Here, we will review the classical protein lesions of the disorder that have provided a road map to etiology and pathogenesis. We will discuss how elucidating the genotype-to-phenotype relationships of familial forms of Alzheimer's disease has highlighted the importance of the misfolding and altered proteostasis of two otherwise soluble proteins, amyloid beta-protein and tau, suggesting mechanism-based therapeutic targets that have led to clinical trials.