Natural oligomers of the amyloid-protein specifically disrupt cognitive function
Natural oligomers of the amyloid-protein specifically disrupt cognitive function
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DOI：
10.1038/nn1372
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发表时间：
2005-01-01
影响因子：
25
通讯作者：
Ashe, KH
中科院分区：
文献类型：
--
作者：
Cleary, JP;Walsh, DM;Ashe, KH
阿尔茨海默病研究中一个尚未解决的中心问题是导致痴呆症的分子实体的性质。在这里，我们提供了第一个直接的实验证据，证明淀粉样蛋白的一个确定的分子物种干扰认知功能。淀粉样蛋白- β的可溶性低聚形式，包括三聚体和二聚体，都是必要和充分的，以一种快速、有效和短暂的方式破坏习得行为；它们造成认知功能受损，但不会引起永久性的神经功能缺陷。尽管β -淀粉样变性长期以来一直被假设会影响认知，但与此或任何其他神经退行性疾病相关的异常折叠蛋白物种此前尚未被分离、生物化学定义，然后特异性表征其对认知功能的影响。具有病理生理特性的离散淀粉样蛋白片段的生化分离为研究阿尔茨海默病和相关神经退行性疾病认知功能障碍的分子机制提供了新的途径。
A central unresolved problem in research on Alzheimer disease is the nature of the molecular entity causing dementia. Here we provide the first direct experimental evidence that a defined molecular species of the amyloid-protein interferes with cognitive function. Soluble oligomeric forms of amyloid-beta, including trimers and dimers, were both necessary and sufficient to disrupt learned behavior in a manner that was rapid, potent and transient; they produced impaired cognitive function without inducing permanent neurological deficits. Although beta-amyloidosis has long been hypothesized to affect cognition, the abnormally folded protein species associated with this or any other neurodegenerative disease has not previously been isolated, defined biochemically and then specifically characterized with regard to its effects on cognitive function. The biochemical isolation of discrete amyloid-moieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.