Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory
Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory
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DOI：
10.1038/nm1782
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发表时间：
2008-08-01
期刊：
影响因子：
82.9
通讯作者：
Selkoe, Dennis J.
中科院分区：
文献类型：
--
作者：
Shankar, Ganesh M.;Li, Shaomin;Selkoe, Dennis J.
阿尔茨海默病对公众健康构成越来越大的威胁。尽管在细胞和动物模型中进行了广泛的研究，但尚未确定人类大脑中存在的病原体并显示其赋予阿尔茨海默病的关键特征。我们直接从阿尔茨海默病患者的大脑皮层中提取可溶性淀粉样β蛋白（Ab）寡聚体。寡聚体有效地抑制长时程增强（LTP），增强长时程抑制（LTD），并降低正常啮齿动物海马树突棘密度。来自阿尔茨海默病脑的可溶性抗体也破坏了正常大鼠学习行为的记忆。这些不同的影响具体归因于Ab二聚体。从机制上讲，代谢型谷氨酸受体是LTD增强所必需的，N-甲基D-天冬氨酸受体是脊柱丢失所必需的。共同施用抗体的N-末端防止LTP和LTD的赤字，而抗体的中间区或C-末端是不太有效的。来自阿尔茨海默病皮质的不溶性淀粉样蛋白斑块核心不损害LTP，除非它们首先被溶解以释放Ab二聚体，这表明斑块核心在很大程度上是无活性的，但螯合具有突触毒性的Ab二聚体。我们的结论是可溶性抗体寡聚体提取阿尔茨海默氏病的大脑有力地损害突触的结构和功能，二聚体是最小的突触毒性物种。
Alzheimer's disease constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of Alzheimer's disease has not been achieved. We extracted soluble amyloid-beta protein (Ab) oligomers directly from the cerebral cortex of subjects with Alzheimer's disease. The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus. Soluble Ab from Alzheimer's disease brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to Ab dimers. Mechanistically, metabotropic glutamate receptors were required for the LTD enhancement, and N-methyl D-aspartate receptors were required for the spine loss. Co-administering antibodies to the Ab N-terminus prevented the LTP and LTD deficits, whereas antibodies to the midregion or C-terminus were less effective. Insoluble amyloid plaque cores from Alzheimer's disease cortex did not impair LTP unless they were first solubilized to release Ab dimers, suggesting that plaque cores are largely inactive but sequester Ab dimers that are synaptotoxic. We conclude that soluble Ab oligomers extracted from Alzheimer's disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species.