圖：功能模塊和通路網絡（海馬區(qū),，前三個階段：aging,，ND_H,，AD_H）
近日,，中國科學院北京基因組研究所“百人計劃”研究員雷紅星開展的“阿爾茲海默癥致病機理的系統(tǒng)生物學研究”取得階段性進展，其研究論文《阿爾茲海默癥中的能量代謝下調是神經元在微環(huán)境下的一種自我保護機制》（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,。
該文對于阿爾茲海默癥的致病機理進行了系統(tǒng)的研究,，基于現(xiàn)有數據及分析結果，提出了一個新的假說,，認為AD中能量代謝的下調是神經元在微環(huán)境中通過降低營養(yǎng)物質和供氧的等級來進行自我保護的一種特殊機制,。進入AD后期，則正是這種較低等級的能量代謝和較高等級的調控和修復壓力產生的矛盾,，觸發(fā)了細胞的凋亡,。
阿爾茲海默癥（Alzheimer's disease, AD）是全球3500萬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,。AD的組織病理學特征是細胞外Aβ淀粉樣沉淀以及神經元內由tau蛋白引起的神經纖維纏結。自1907年AD被首次描述以來,，無數科學家付出了巨大努力,，卻始終無法準確地解釋AD的致病機理。在淀粉樣蛋白假說（Amyloid Hypothesis）中,，Aβ蛋白聚集被認為是神經元退化,、凋亡直至癡呆產生的觸發(fā)因素，但是AD是如何一步步發(fā)展致病的,，卻仍是一個有待深入研究的問題,。在過去的十年里，全基因組基因芯片技術被廣泛應用到AD致病機理的研究中,，基于功能富集,，通路和網絡擾動，一些公共芯片數據被反復分析,。但是由于大多數的芯片實驗都是針對AD后期進行的,，這樣很難推斷出AD的致病機理。
為了研究AD的進展機制,，雷紅星研究員及其研究團隊對于AD不同疾病階段的芯片數據進行了全面地收集,、過濾以及整合。由于衰老通常被認為是LOAD的主要致病因素,，因此,，正常衰老的樣本被視為AD的前兆階段進行分析,。通過對AD不同階段芯片數據的整合分析,，顯示了AD發(fā)展進程中細胞機器是如何一步步損壞的,。在AD早期，Aβ蛋白聚集會導致生物合成和能量代謝的下調,，而隨著疾病的發(fā)展,，會進一步導致信號轉導作用的增強。在疾病的晚期,，細胞凋亡作用則表現(xiàn)比較顯著,。通常來說，能量代謝的下調被認為是氧化應激所導致的線粒體損害造成的,，然而,，對于AD不同疾病階段的研究，并沒有發(fā)現(xiàn)氧化應激反應的增強和電子傳遞鏈的下調,。由此,，研究人員提出假設，認為AD中能量代謝的下調是神經元在微環(huán)境中通過降低營養(yǎng)物質和供氧的等級來進行自我保護的一種特殊機制,。進入AD后期,，則正是這種較低等級的能量代謝和較高等級的調控和修復壓力產生的矛盾，觸發(fā)了細胞的凋亡,。
這一新的假說對于AD致病機理的研究起到了積極的推動作用,，為AD的藥物設計也開辟了新的思路。(生物谷Bioon.com）
>>延伸閱讀: JAD：科學家發(fā)現(xiàn)與老年癡呆癥相關的新蛋白c-Abl
>>延伸閱讀: 血管增生導致阿爾茨海默病
>>延伸閱讀: Nature Cell Biology：阿爾茨海默氏癥蛋白可能與朊病毒性質相似
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.
