The neuronal adaptor protein X11β reduces amyloid β-protein levels and amyloid plaque formation in the brains of transgenic mice
The neuronal adaptor protein X11β reduces amyloid β-protein levels and amyloid plaque formation in the brains of transgenic mice
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DOI：
10.1074/jbc.m405602200
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发表时间：
2004-11-19
影响因子：
4.8
通讯作者：
Miller, CCJ
中科院分区：
文献类型：
--
作者：
Lee, JH;Lau, KF;Miller, CCJ
大脑淀粉样蛋白（Abeta）的积累被认为是阿尔茨海默病发病过程的一部分。β是由淀粉样前体蛋白（APP）裂解而来的。APP是一种1型跨膜蛋白，其羧基末端胞内结构域与神经元接头蛋白X11beta结合。X11beta已被证明可以抑制培养中转染的非神经元细胞中β的产生。然而，在大脑体内是否也是如此，以及X11beta是否也能抑制Abeta作为淀粉样斑块的沉积，目前尚不清楚。本研究表明，在转基因APPswe Tg2576小鼠（阿尔茨海默病淀粉样蛋白病理模型）中，神经元中x11β的转基因过表达导致大脑β水平下降。此外，在这些APPswe小鼠中，x11β的过度表达延缓了淀粉样斑块的形成。我们的研究结果表明，调节x11 β功能可能是预防阿尔茨海默病淀粉样蛋白病理的一种新的治疗方法。
Accumulation of cerebral amyloid beta-protein (Abeta) is believed to be part of the pathogenic process in Alzheimer's disease. Abeta is derived by proteolytic cleavage from a precursor protein, the amyloid precursor protein (APP). APP is a type-1 membrane-spanning protein, and its carboxyl-terminal intracellular domain binds to X11beta, a neuronal adaptor protein. X11beta has been shown to inhibit the production of Abeta in transfected non-neuronal cells in culture. However, whether this is also the case in vivo in the brain and whether X11beta can also inhibit the deposition of Abeta as amyloid plaques is not known. Here we show that transgenic overexpression of X11beta in neurons leads to a decrease in cerebral Abeta levels in transgenic APPswe Tg2576 mice that are a model of the amyloid pathology of Alzheimer's disease. Moreover, overexpression of X11beta retards amyloid plaque formation in these APPswe mice. Our findings suggest that modulation of X11beta function may represent a novel therapeutic approach for preventing the amyloid pathology of Alzheimer's disease.