Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice
Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice
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DOI：
10.1016/j.neurobiolaging.2011.11.006
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发表时间：
2012-06-01
影响因子：
4.2
通讯作者：
Tanila, Heikki
中科院分区：
文献类型：
--
作者：
Kemppainen, Susanna;Rantamaki, Tomi;Tanila, Heikki
脑源性神经营养因子（BDNF）在神经元可塑性、学习和记忆中起重要作用。据报道，在阿尔茨海默病中，BDNF及其主要受体TrkB（TrkB.TK）的水平降低，而截短的TrkB（TrkB. T1）的水平升高。我们在这里表明，与淀粉样蛋白β孵育增加TrkB. T1受体水平和降低TrkB.TK水平在原代神经元。在体内，与TrkB. TK相比，APPswe/PS1 dE 9转基因小鼠（APdE 9）显示出皮质而非海马TrkB.T1受体水平的年龄依赖性相对增加。为了研究TrkB亚型在阿尔茨海默病中的作用，我们将AP小鼠与过表达截短的TrkB. T1受体（T1）或全长TrkB.TK亚型的小鼠杂交。TrkB.T1在APdE 9小鼠中的过表达加重了其空间记忆障碍，而TrkB.TK的过表达减轻了其空间记忆障碍。这些数据表明，淀粉样蛋白β在体外和体内改变了TrkB亚型之间的比例，有利于显性阴性的TrkB.T1亚型，并支持BDNF通过TrkB信号传导在阿尔茨海默病的病理生理学和认知缺陷中的作用。(C)2012 Elsevier Inc. All rights reserved.
Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory. Levels of BDNF and its main receptor TrkB (TrkB.TK) have been reported to be decreased while the levels of the truncated TrkB (TrkB.T1) are increased in Alzheimer's disease. We show here that incubation with amyloid-beta increased TrkB.T1 receptor levels and decreased TrkB.TK levels in primary neurons. In vivo, APPswe/PS1dE9 transgenic mice (APdE9) showed an age-dependent relative increase in cortical but not hippocampal TrkB.T1 receptor levels compared with TrkB.TK. To investigate the role of TrkB isoforms in Alzheimer's disease, we crossed AP mice with mice overexpressing the truncated TrkB.T1 receptor (T1) or the full-length TrkB.TK isoform. Overexpression of TrkB.T1 in APdE9 mice exacerbated their spatial memory impairment while the overexpression of TrkB.TK alleviated it. These data suggest that amyloid-beta changes the ratio between TrkB isoforms in favor of the dominant-negative TrkB.T1 isoform both in vitro and in vivo and supports the role of BDNF signaling through TrkB in the pathophysiology and cognitive deficits of Alzheimer's disease. (C) 2012 Elsevier Inc. All rights reserved.