2012年11月21日 讯 /生物谷BIOON/ --一项发表在11月20日Molecular Psychiatry杂志上的研究揭示了推动阿尔茨海默氏症患者大脑变化的关键性分子途径,该研究证实了这条信号分子途径可被利用来开发对抗疾病的药物。
阿尔茨海默病即所谓的老年痴呆症。是一种进行性发展的致死性神经退行性疾病,临床表现为认知和记忆功能不断恶化,日常生活能力进行性减退,并有各种神经精神症状和行为障碍。
阿尔茨海默病主要表现为脑细胞的广泛死亡,患者脑中有广泛的神经元纤维缠结,轴突缠结形成老年斑,阿尔茨海默病患者脑内还存在β-淀粉样蛋白过度积聚。目前,该类疾病的发病确切机制仍然有点神秘。
近日,伦敦大学国王学院精神病学研究所研究人员在实验室中培养的鼠脑细胞中发现,淀粉样蛋白的存在改变了这些细胞中的凝聚素。凝聚素的作用是切换信号转导通路以驱动细胞内tau蛋白的变化。当此信号转导通路长期处于开启状态时,研究人员在小鼠疾病模型中观察到了认知缺陷。
该研究也分析了凝聚素的激活是否只是在阿尔茨海默氏症患者的大脑中存在,而在其他形式的痴呆症患者大脑中检测不到。
凝聚素调控的分子途径为DKK1-WNT信号转导通路,该信号通路涉及到若干不同的分子,可能被证明用于开发新的药物。目前阿尔茨海默氏症的治疗都集中在减轻症状,而没有治疗方法来防止疾病的进展。
研究负责人Simon Lovestone教授说:我们已证实阻断这一信号通路,我们可以阻止淀粉样蛋白对脑细胞的毒性影响。我们相信,如果我们可以抑制阿尔茨海默氏症患者大脑中该信号通路的活动,那么我们可能有机会遏制疾病的发展。(生物谷:Bioon.com)
doi:10.1038/mp.2012.163
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Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt–PCP–JNK pathway.
R Killick, E M Ribe, R Al-Shawi, B Malik, C Hooper, C Fernandes, R Dobson, P M Nolan, A Lourdusamy, S Furney, K Lin, G Breen, R Wroe, A W M To, K Leroy, M Causevic, A Usardi, M Robinson, W Noble, R Williamson, K Lunnon, S Kellie, C H Reynolds, C Bazenet, A Hodges, J-P Brion, J Stephenson, J Paul Simons, Simon Lovestone.
Although the mechanism of Aβ action in the pathogenesis of Alzheimer’s disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aβ neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aβ/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aβ toxicity and DKK1 upregulation and, conversely, Aβ increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1. To further elucidate how the clusterin-dependent induction of Dkk1 by Aβ mediates neurotoxicity, we measured the effects of Aβ and Dkk1 protein on whole-genome expression in primary neurons, finding a common pathway suggestive of activation of wnt–planar cell polarity (PCP)–c-Jun N-terminal kinase (JNK) signalling leading to the induction of genes including EGR1 (early growth response-1), NAB2 (Ngfi-A-binding protein-2) and KLF10 (Krüppel-like factor-10) that, when individually silenced, protected against Aβ neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aβ-induced pathway and resulted in age-dependent increases in tau phosphorylation in hippocampus and cognitive impairment. Furthermore, we show that this Dkk1/wnt–PCP–JNK pathway is active in an Aβ-based mouse model of AD and in AD brain, but not in a tau-based mouse model or in frontotemporal dementia brain. Thus, we have identified a pathway whereby Aβ induces a clusterin/p53/Dkk1/wnt–PCP–JNK pathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, thereby providing new mechanistic insights into the action of Aβ in neurodegenerative diseases.