Insulin growth factor binding protein 7 is a novel target to treat dementia
Insulin growth factor binding protein 7 is a novel target to treat dementia
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DOI：
10.1016/j.nbd.2013.09.011
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发表时间：
2014-02-01
影响因子：
6.1
通讯作者：
Fischer, Andre
中科院分区：
文献类型：
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作者：
Agbemenyah, Hope Y.;Agis-Balboa, Roberto C.;Fischer, Andre
阿尔茨海默病(AD)是老年人最常见的痴呆症，但目前尚无有效的治疗策略。这也是由于散发性阿尔茨海默病发病的病理机制仍未被充分了解，在个体水平上可能存在差异。一些危险因素，如胰岛素样肽(ILP)信号的改变与AD有关，调节ILP系统已被讨论为一种潜在的治疗途径。在这里，我们展示了胰岛素样生长因子结合蛋白7(IGFBP7)，一种减弱ILPS功能的蛋白质，在AD患者的大脑和AD小鼠模型中上调，这一过程涉及DNA甲基化改变，并与ILP信号减弱相一致。模拟野生型小鼠的阿尔茨海默病情况，通过增加海马区IGFBP7水平导致记忆巩固受损。一贯地，抑制IGFBP7在发展为AD样记忆障碍的小鼠中的功能可以恢复联想学习行为。这些数据表明，IGFBP7是记忆巩固的关键调节因子，可能作为AD的生物标志物。靶向IGFBP7有望成为治疗AD患者的新途径。(C)2013 Elsevier Inc.保留所有权利。
Alzheimer's disease (AD) is the most common form of dementia in the elderly but effective therapeutic strategies to treat AD are not yet available. This is also due to the fact that the pathological mechanisms that drive the pathogenesis of sporadic AD are still not sufficiently understood and may differ on the individual level. Several risk factors such as altered insulin-like peptide (ILP) signaling have been linked to AD and modulating the ILP system has been discussed as a potential therapeutic avenue. Here we show that insulin-like growth factor binding protein 7 (IGFBP7), a protein that attenuates the function of ILPs, is up-regulated in the brains of AD patients and in a mouse model for AD via a process that involves altered DNA-methylation and coincides with decreased ILP signaling. Mimicking the AD-situation in wild type mice, by increasing hippocampal IGFBP7 levels leads to impaired memory consolidation. Consistently, inhibiting IGFBP7 function in mice that develop AD-like memory impairment reinstates associative learning behavior. These data suggest that IGFBP7 is a critical regulator of memory consolidation and might be used as a biomarker for AD. Targeting IGFBP7 could be a novel therapeutic avenue for the treatment of AD patients. (C) 2013 Elsevier Inc. All rights reserved.