X11β rescues memory and long-term potentiation deficits in Alzheimer's disease APPswe Tg2576 mice
X11β rescues memory and long-term potentiation deficits in Alzheimer's disease APPswe Tg2576 mice
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DOI：
10.1093/hmg/ddp408
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发表时间：
2009-12-01
影响因子：
3.5
通讯作者：
McLoughlin, Declan M.
中科院分区：
文献类型：
--
作者：
Mitchell, Jacqueline C.;Ariff, Belall B.;McLoughlin, Declan M.
淀粉样β蛋白（A β）的产生和沉积增加被认为是阿尔茨海默病的关键致病事件。因此，降低脑A β水平的途径代表了阿尔茨海默病的潜在治疗靶点。X11 β是一种神经元衔接蛋白，与淀粉样前体蛋白（APP）的胞内结构域结合。在许多实验系统中，X11 β的过表达抑制A β的产生。然而，X11 β过表达诱导的APP加工和A β产生的这些变化是否也对记忆和突触可塑性产生有益影响尚不清楚。我们在这里报告说，X11 β介导的大脑A β的减少与认知和在老年APPswe Tg2576转基因小鼠模型阿尔茨海默氏病的淀粉样病变在体内的长时程增强的正常化。X11 β本身的过度表达对小鼠行为没有可检测到的不良影响。这些发现支持了这样的观点，即调节X11 β功能是阿尔茨海默病中A β介导的神经元功能障碍的治疗靶点。
Increased production and deposition of amyloid beta-protein (A beta) are believed to be key pathogenic events in Alzheimer's disease. As such, routes for lowering cerebral A beta levels represent potential therapeutic targets for Alzheimer's disease. X11 beta is a neuronal adaptor protein that binds to the intracellular domain of the amyloid precursor protein (APP). Overexpression of X11 beta inhibits A beta production in a number of experimental systems. However, whether these changes to APP processing and A beta production induced by X11 beta overexpression also induce beneficial effects to memory and synaptic plasticity are not known. We report here that X11 beta-mediated reduction in cerebral A beta is associated with normalization of both cognition and in vivo long-term potentiation in aged APPswe Tg2576 transgenic mice that model the amyloid pathology of Alzheimer's disease. Overexpression of X11 beta itself has no detectable adverse effects upon mouse behaviour. These findings support the notion that modulation of X11 beta function represents a therapeutic target for A beta-mediated neuronal dysfunction in Alzheimer's disease.