圖：功能模塊和通路網(wǎng)絡(luò)（海馬區(qū),，前三個(gè)階段：aging,，ND_H,，AD_H）
近日,，中國(guó)科學(xué)院北京基因組研究所“百人計(jì)劃”研究員雷紅星開(kāi)展的“阿爾茲海默癥致病機(jī)理的系統(tǒng)生物學(xué)研究”取得階段性進(jìn)展，其研究論文《阿爾茲海默癥中的能量代謝下調(diào)是神經(jīng)元在微環(huán)境下的一種自我保護(hù)機(jī)制》（Down-Regulation of Energy Metabolism in Alzheimer's Disease is a Protective Response of Neurons to the Microenvironment）于2011年10月在Journal of Alzheimer's Disease雜志上發(fā)表,。
該文對(duì)于阿爾茲海默癥的致病機(jī)理進(jìn)行了系統(tǒng)的研究,，基于現(xiàn)有數(shù)據(jù)及分析結(jié)果，提出了一個(gè)新的假說(shuō),，認(rèn)為AD中能量代謝的下調(diào)是神經(jīng)元在微環(huán)境中通過(guò)降低營(yíng)養(yǎng)物質(zhì)和供氧的等級(jí)來(lái)進(jìn)行自我保護(hù)的一種特殊機(jī)制,。進(jìn)入AD后期，則正是這種較低等級(jí)的能量代謝和較高等級(jí)的調(diào)控和修復(fù)壓力產(chǎn)生的矛盾,，觸發(fā)了細(xì)胞的凋亡,。
阿爾茲海默癥（Alzheimer's disease, AD）是全球3500萬(wàn)癡呆患者中最主要的發(fā)病形式，其中又以遲發(fā)型老年癡呆（late-onset AD,，LOAD）最為常見(jiàn),。AD的組織病理學(xué)特征是細(xì)胞外Aβ淀粉樣沉淀以及神經(jīng)元內(nèi)由tau蛋白引起的神經(jīng)纖維纏結(jié)。自1907年AD被首次描述以來(lái),，無(wú)數(shù)科學(xué)家付出了巨大努力，卻始終無(wú)法準(zhǔn)確地解釋AD的致病機(jī)理,。在淀粉樣蛋白假說(shuō)（Amyloid Hypothesis）中,，Aβ蛋白聚集被認(rèn)為是神經(jīng)元退化、凋亡直至癡呆產(chǎn)生的觸發(fā)因素,，但是AD是如何一步步發(fā)展致病的,，卻仍是一個(gè)有待深入研究的問(wèn)題。在過(guò)去的十年里,，全基因組基因芯片技術(shù)被廣泛應(yīng)用到AD致病機(jī)理的研究中,，基于功能富集，通路和網(wǎng)絡(luò)擾動(dòng),，一些公共芯片數(shù)據(jù)被反復(fù)分析,。但是由于大多數(shù)的芯片實(shí)驗(yàn)都是針對(duì)AD后期進(jìn)行的，這樣很難推斷出AD的致病機(jī)理,。
為了研究AD的進(jìn)展機(jī)制,，雷紅星研究員及其研究團(tuán)隊(duì)對(duì)于AD不同疾病階段的芯片數(shù)據(jù)進(jìn)行了全面地收集、過(guò)濾以及整合,。由于衰老通常被認(rèn)為是LOAD的主要致病因素,，因此，正常衰老的樣本被視為AD的前兆階段進(jìn)行分析,。通過(guò)對(duì)AD不同階段芯片數(shù)據(jù)的整合分析,，顯示了AD發(fā)展進(jìn)程中細(xì)胞機(jī)器是如何一步步損壞的,。在AD早期，Aβ蛋白聚集會(huì)導(dǎo)致生物合成和能量代謝的下調(diào),，而隨著疾病的發(fā)展,，會(huì)進(jìn)一步導(dǎo)致信號(hào)轉(zhuǎn)導(dǎo)作用的增強(qiáng)。在疾病的晚期,，細(xì)胞凋亡作用則表現(xiàn)比較顯著,。通常來(lái)說(shuō)，能量代謝的下調(diào)被認(rèn)為是氧化應(yīng)激所導(dǎo)致的線(xiàn)粒體損害造成的,，然而,，對(duì)于AD不同疾病階段的研究，并沒(méi)有發(fā)現(xiàn)氧化應(yīng)激反應(yīng)的增強(qiáng)和電子傳遞鏈的下調(diào),。由此,，研究人員提出假設(shè)，認(rèn)為AD中能量代謝的下調(diào)是神經(jīng)元在微環(huán)境中通過(guò)降低營(yíng)養(yǎng)物質(zhì)和供氧的等級(jí)來(lái)進(jìn)行自我保護(hù)的一種特殊機(jī)制,。進(jìn)入AD后期,，則正是這種較低等級(jí)的能量代謝和較高等級(jí)的調(diào)控和修復(fù)壓力產(chǎn)生的矛盾，觸發(fā)了細(xì)胞的凋亡,。
這一新的假說(shuō)對(duì)于AD致病機(jī)理的研究起到了積極的推動(dòng)作用,，為AD的藥物設(shè)計(jì)也開(kāi)辟了新的思路。(生物谷Bioon.com）
>>延伸閱讀: JAD：科學(xué)家發(fā)現(xiàn)與老年癡呆癥相關(guān)的新蛋白c-Abl
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doi:10.3233/JAD-2011-111313
PMC:
PMID:
Down-Regulation of Energy Metabolism in Alzheimer's Disease is a Protective Response of Neurons to the Microenvironment
Authors
Jiya Sun1, 2, Xuemei Feng1, Dapeng Liang1, 2, Yong Duan3, 4, Hongxing Lei1, 3
1CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
2Graduate University, Chinese Academy of Sciences, Beijing, China
3UC Davis Genome Center and Department of Biomedical Engineering, Davis, CA, USA
4College of Physics, Huazhong University of Science and Technology, Wuhan, China
Abstract
A central issue in the field of Alzheimer's disease (AD) is to separate the cause from the consequence among many observed pathological features, which may be resolved by studying the time evolution of these features at distinctive stages. In this work, comprehensive analyses on transcriptome studies of human postmortem brain tissues from AD patients at distinctive stages revealed stepwise breakdown of the cellular machinery during the progression of AD. At the early stage of AD, the accumulation of amyloid-β oligomers and amyloid plaques leads to the down-regulation of biosynthesis and energy metabolism. At the intermediate stage, the progression of the disease leads to enhanced signal transduction, while the late stage is characterized by the elevated apoptosis. The down-regulation of energy metabolism in AD has been considered by many as a consequence of mitochondrion damage due to oxidative stress. However, the non-existence of enhanced response to oxidative stress and the revelation of intriguing down-regulation patterns of the electron-transport chain at different stages suggest otherwise. In contrast to the damage-themed hypothesis, we propose that the down-regulation of energy metabolism in AD is a protective response of the neurons to the reduced level of nutrient and oxygen supply in the microenvironment. The elevated apoptosis at the late stage of AD is triggered by the conflict between the low level of energy metabolism and high level of regulatory and repair burden. This new hypothesis has significant implication for pharmaceutical intervention of Alzheimer's disease.
