2012年11月21日 訊 /生物谷BIOON/ --一項發(fā)表在11月20日Molecular Psychiatry雜志上的研究揭示了推動阿爾茨海默氏癥患者大腦變化的關(guān)鍵性分子途徑,，該研究證實了這條信號分子途徑可被利用來開發(fā)對抗疾病的藥物,。
阿爾茨海默病即所謂的老年癡呆癥。是一種進行性發(fā)展的致死性神經(jīng)退行性疾病,，臨床表現(xiàn)為認知和記憶功能不斷惡化,，日常生活能力進行性減退,，并有各種神經(jīng)精神癥狀和行為障礙。
阿爾茨海默病主要表現(xiàn)為腦細胞的廣泛死亡,，患者腦中有廣泛的神經(jīng)元纖維纏結(jié),，軸突纏結(jié)形成老年斑，阿爾茨海默病患者腦內(nèi)還存在β-淀粉樣蛋白過度積聚,。目前,，該類疾病的發(fā)病確切機制仍然有點神秘。
近日，倫敦大學國王學院精神病學研究所研究人員在實驗室中培養(yǎng)的鼠腦細胞中發(fā)現(xiàn),，淀粉樣蛋白的存在改變了這些細胞中的凝聚素,。凝聚素的作用是切換信號轉(zhuǎn)導通路以驅(qū)動細胞內(nèi)tau蛋白的變化。當此信號轉(zhuǎn)導通路長期處于開啟狀態(tài)時,，研究人員在小鼠疾病模型中觀察到了認知缺陷,。
該研究也分析了凝聚素的激活是否只是在阿爾茨海默氏癥患者的大腦中存在，而在其他形式的癡呆癥患者大腦中檢測不到,。
凝聚素調(diào)控的分子途徑為DKK1-WNT信號轉(zhuǎn)導通路,，該信號通路涉及到若干不同的分子，可能被證明用于開發(fā)新的藥物,。目前阿爾茨海默氏癥的治療都集中在減輕癥狀,，而沒有治療方法來防止疾病的進展。
研究負責人Simon Lovestone教授說：我們已證實阻斷這一信號通路,，我們可以阻止淀粉樣蛋白對腦細胞的毒性影響,。我們相信，如果我們可以抑制阿爾茨海默氏癥患者大腦中該信號通路的活動,，那么我們可能有機會遏制疾病的發(fā)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.
