Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer's disease
Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer's disease
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DOI：
10.1038/nature06616
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发表时间：
2008-02-07
期刊：
影响因子：
64.8
通讯作者：
Hyman, Bradley T.
中科院分区：
文献类型：
--
作者：
Meyer-Luehmann, Melanie;Spires-Jones, Tara L.;Hyman, Bradley T.
老年斑在阿尔茨海默病患者的大脑中积累了数十年。阿尔茨海默病的淀粉样蛋白假说的基本原则是淀粉样蛋白-β的沉积先于并诱导痴呆症基础的神经元异常（1）。然而，这一观点受到了质疑，有人认为轴突运输和形态异常的改变先于并导致老年斑（2）。小胶质细胞在加速或延缓这些过程中的作用尚不确定。为了研究斑块形成与局部神经炎结构变化之间的时间关系，我们使用纵向体内多光子显微镜对年轻的APPswe/PS1 d9 xYFP（B6 C3-YFP）转基因小鼠进行连续成像（3）。在这里，我们表明，斑块形成非常迅速，超过24小时。在新斑块出现的1-2天内，小胶质细胞被激活并被招募到该部位。进行性神经炎性变化随之而来，导致在接下来的几天到几周内越来越畸形的神经突。这些数据确定斑块是神经炎病理学的关键介质。
Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer's disease. A fundamental tenet of the amyloid hypothesis of Alzheimer's disease is that the deposition of amyloid-beta precedes and induces the neuronal abnormalities that underlie dementia(1). This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques(2). The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/ PS1d9xYFP ( B6C3-YFP) transgenic mice(3). Here we show that plaques form extraordinarily quickly, over 24 h. Within 1-2 days of a new plaque's appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.