Department of Translational Neuroscience, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
Clinical Research Center for Dementia, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
Int J Mol Sci. 2020 Feb 19;21(4):1413. doi: 10.3390/ijms21041413.
Alzheimer's disease is believed to begin with synaptic dysfunction caused by soluble Aβ oligomers. When this oligomer hypothesis was proposed in 2002, there was no direct evidence that Aβ oligomers actually disrupt synaptic function to cause cognitive impairment in humans. In patient brains, both soluble and insoluble Aβ species always coexist, and therefore it is difficult to determine which pathologies are caused by Aβ oligomers and which are caused by amyloid fibrils. Thus, no validity of the oligomer hypothesis was available until the Osaka mutation was discovered. This mutation, which was found in a Japanese pedigree of familial Alzheimer's disease, is the deletion of codon 693 of APP gene, resulting in mutant Aβ lacking the 22nd glutamate. Only homozygous carriers suffer from dementia. In vitro studies revealed that this mutation has a very unique character that accelerates Aβ oligomerization but does not form amyloid fibrils. Model mice expressing this mutation demonstrated that all pathologies of Alzheimer's disease can be induced by Aβ oligomers alone. In this review, we describe the story behind the discovery of the Osaka mutation, summarize the mutant's phenotypes, and propose a mechanism of its recessive inheritance.
阿尔茨海默病被认为始于可溶 Aβ 寡聚物引起的突触功能障碍。当 2002 年提出寡聚体假说时，尚无直接证据表明 Aβ 寡聚体实际上会破坏突触功能，从而导致人类认知障碍。在患者大脑中，可溶性和不溶性 Aβ 物种总是共存的，因此很难确定哪些病变是由 Aβ 寡聚体引起的，哪些是由淀粉样纤维引起的。因此，直到发现大阪突变，寡聚体假说才具有有效性。该突变是在一个日本家族性阿尔茨海默病谱系中发现的，是 APP 基因的 693 密码子缺失，导致突变的 Aβ 缺乏第 22 个谷氨酸。只有纯合子携带者会出现痴呆。体外研究表明，该突变具有非常独特的特征，可加速 Aβ 寡聚化，但不会形成淀粉样纤维。表达该突变的模型小鼠表明，阿尔茨海默病的所有病理变化都可以仅由 Aβ 寡聚体诱导。在这篇综述中，我们描述了发现大阪突变的背后故事，总结了突变体的表型，并提出了其隐性遗传的机制。
