MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, London SE5 8AF, UK.
Hum Mol Genet. 2009 Dec 1;18(23):4492-500. doi: 10.1093/hmg/ddp408. Epub 2009 Sep 10.
Increased production and deposition of amyloid beta-protein (Abeta) are believed to be key pathogenic events in Alzheimer's disease. As such, routes for lowering cerebral Abeta levels represent potential therapeutic targets for Alzheimer's disease. X11beta is a neuronal adaptor protein that binds to the intracellular domain of the amyloid precursor protein (APP). Overexpression of X11beta inhibits Abeta production in a number of experimental systems. However, whether these changes to APP processing and Abeta production induced by X11beta overexpression also induce beneficial effects to memory and synaptic plasticity are not known. We report here that X11beta-mediated reduction in cerebral Abeta 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 X11beta itself has no detectable adverse effects upon mouse behaviour. These findings support the notion that modulation of X11beta function represents a therapeutic target for Abeta-mediated neuronal dysfunction in Alzheimer's disease.
淀粉样β蛋白（Abeta）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，降低脑内 Abeta 水平的途径代表了阿尔茨海默病的潜在治疗靶点。X11β 是一种神经元衔接蛋白，可与淀粉样前体蛋白（APP）的细胞内结构域结合。在许多实验系统中，X11β 的过表达可抑制 Abeta 的产生。然而，X11β 过表达引起的 APP 加工和 Abeta 产生的这些变化是否也会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，X11β 介导的脑内 Abeta 减少与阿尔茨海默病模型 APPswe Tg2576 转基因小鼠的认知和体内长时程增强的正常化有关。X11β 的过表达本身对小鼠行为没有可检测到的不良影响。这些发现支持这样一种观点，即调节 X11β 的功能代表了阿尔茨海默病中 Abeta 介导的神经元功能障碍的治疗靶点。
