Blood-derived amyloid-β protein induces Alzheimer's disease pathologies
Blood-derived amyloid-β protein induces Alzheimer's disease pathologies
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血液来源的淀粉样β蛋白诱发阿尔茨海默病病理
DOI：
10.1038/mp.2017.204
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发表时间：
2018-09-01
影响因子：
11
通讯作者：
Wang, Y-J
中科院分区：
文献类型：
--
作者：
Bu, X-L;Xiang, Y.;Wang, Y-J
淀粉样β蛋白（A β）在阿尔茨海默病（AD）的发病机制中起着关键作用。据信，沉积在大脑中的A β来源于脑组织本身。然而，A β在大脑和外周组织中产生。循环A β是否有助于脑AD型病理仍在很大程度上未知。在这项研究中，我们使用APPswe/PS1 dE 9转基因AD小鼠与其野生型同窝小鼠之间的联体共生模型，观察到来自转基因AD模型小鼠的人A β进入循环并在野生型小鼠的脑中积聚，并在联体共生12个月后形成脑淀粉样血管病和A β斑块。在联体野生型小鼠的大脑中发现了与A β积累相关的AD型病理学，包括tau过度磷酸化、神经变性、神经炎症和微出血。更重要的是，海马CA 1长时程增强在联体野生型小鼠中明显受损。据我们所知，我们的研究首次揭示了血液来源的A β可以进入大脑，形成A β相关的病理并诱导神经元的功能缺陷。我们的研究为AD发病机制提供了新的见解，并提供了证据，支持通过靶向大脑和外周的A β代谢来开发AD治疗方法。
The amyloid-beta protein (A beta) protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). It is believed that A beta deposited in the brain originates from the brain tissue itself. However, A beta is generated in both brain and peripheral tissues. Whether circulating A beta contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human A beta originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and A beta plaques after a 12-month period of parabiosis. AD-type pathologies related to the A beta accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived A beta can enter the brain, form the A beta-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting A beta metabolism in both the brain and the periphery.