阿爾茨海默病（Alzheimer’s disease,，AD）是一種以記憶力損傷為表現(xiàn)的進(jìn)行性神經(jīng)退行性病變,，Ab引起的神經(jīng)退行性病變被認(rèn)為是導(dǎo)致AD的關(guān)鍵因素。隨著老齡化社會(huì)的到來,，我國(guó)AD的發(fā)病率與日俱增,，然而迄今為止，市場(chǎng)依然缺乏有效的治療AD的藥物,。8月7日,，Journal of Neuroscience（《神經(jīng)科學(xué)雜志》）在線發(fā)表了中科院上海藥物研究所沈旭、胡立宏和蔣華良三個(gè)研究小組共同合作完成的研究成果,。該研究首次發(fā)現(xiàn)天然產(chǎn)物“牛蒡子苷元”能夠有效改善AD小鼠的記憶損傷,。(J. Neurosci.,，2013,，33，13138-49.)
針對(duì)目前基于Ab為靶點(diǎn)的抗AD藥物研發(fā)的困境,，研究人員首次采用不同于長(zhǎng)期以來的“酶活調(diào)節(jié)”模式而以“蛋白表達(dá)通路調(diào)控”策略建立了基于“一石二鳥”的抗AD藥物篩選平臺(tái)——既能抑制Ab產(chǎn)生又能增加Ab清除,，發(fā)現(xiàn)了天然活性分子“牛蒡子苷元（Arctigenin， ATG）”,。研究表明,，給予ATG的AD模型小鼠出現(xiàn)明顯的腦內(nèi)蛋白沉淀斑減少，并且小鼠記憶力損傷得到明顯恢復(fù),。機(jī)制研究結(jié)果顯示ATG調(diào)節(jié)AMPK及AKT/mTOR通路以增強(qiáng)自噬作用,，從而增加Ab清除；另一方面,，ATG還通過抑制PERK/eIF2a-P通路以減少BACE1的翻譯進(jìn)而抑制Ab生成,。另外，AMPK和mTOR為抑制衰老和老年化的重要靶點(diǎn),，因此該研究還提示ATG具有通過抑制衰老和老年化而起到治療AD的作用,。
該項(xiàng)研究不僅為抗AD創(chuàng)新藥物的研發(fā)提供了新的研究策略，而且為基于“牛蒡子苷元”的抗AD藥物進(jìn)一步的開發(fā)提供了重要依據(jù),。牛蒡子是牛蒡的果實(shí),，牛蒡?yàn)槭a(chǎn)于日本和我國(guó)多地區(qū)的一種蔬菜,。2011年，沈旭和胡立宏研究小組曾合作研究發(fā)現(xiàn)“牛蒡子苷元”具有提高機(jī)體抗疲勞的功能 (Plos One,， 2011),。
該項(xiàng)研究由博士后朱志遠(yuǎn)、博士生顏建明,、姜維和黎陳靜助理研究員等完成,。相關(guān)成果已申請(qǐng)了專利。（生物谷Bioon.com）
doi:10.1523/JNEUROSCI.4790-12.2013
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Arctigenin Effectively Ameliorates Memory Impairment in Alzheimer's Disease Model Mice Targeting Both β-Amyloid Production and Clearance
Zhiyuan Zhu, Jianming Yan, Wei Jiang, Xin-gang Yao, Jing Chen, Lili Chen, Chenjing Li, Lihong Hu, Hualiang Jiang, and Xu Shen
Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery.
