图：功能模块和通路网络（海马区，前三个阶段：aging，ND_H，AD_H）
近日，中国科学院北京基因组研究所“百人计划”研究员雷红星开展的“阿尔兹海默症致病机理的系统生物学研究”取得阶段性进展，其研究论文《阿尔兹海默症中的能量代谢下调是神经元在微环境下的一种自我保护机制》（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杂志上发表。
该文对于阿尔兹海默症的致病机理进行了系统的研究，基于现有数据及分析结果，提出了一个新的假说，认为AD中能量代谢的下调是神经元在微环境中通过降低营养物质和供氧的等级来进行自我保护的一种特殊机制。进入AD后期，则正是这种较低等级的能量代谢和较高等级的调控和修复压力产生的矛盾，触发了细胞的凋亡。
阿尔兹海默症（Alzheimer's disease, AD）是全球3500万痴呆患者中最主要的发病形式，其中又以迟发型老年痴呆（late-onset AD，LOAD）最为常见。AD的组织病理学特征是细胞外Aβ淀粉样沉淀以及神经元内由tau蛋白引起的神经纤维缠结。自1907年AD被首次描述以来，无数科学家付出了巨大努力，却始终无法准确地解释AD的致病机理。在淀粉样蛋白假说（Amyloid Hypothesis）中，Aβ蛋白聚集被认为是神经元退化、凋亡直至痴呆产生的触发因素，但是AD是如何一步步发展致病的，却仍是一个有待深入研究的问题。在过去的十年里，全基因组基因芯片技术被广泛应用到AD致病机理的研究中，基于功能富集，通路和网络扰动，一些公共芯片数据被反复分析。但是由于大多数的芯片实验都是针对AD后期进行的，这样很难推断出AD的致病机理。
为了研究AD的进展机制，雷红星研究员及其研究团队对于AD不同疾病阶段的芯片数据进行了全面地收集、过滤以及整合。由于衰老通常被认为是LOAD的主要致病因素，因此，正常衰老的样本被视为AD的前兆阶段进行分析。通过对AD不同阶段芯片数据的整合分析，显示了AD发展进程中细胞机器是如何一步步损坏的。在AD早期，Aβ蛋白聚集会导致生物合成和能量代谢的下调，而随着疾病的发展，会进一步导致信号转导作用的增强。在疾病的晚期，细胞凋亡作用则表现比较显著。通常来说，能量代谢的下调被认为是氧化应激所导致的线粒体损害造成的，然而，对于AD不同疾病阶段的研究，并没有发现氧化应激反应的增强和电子传递链的下调。由此，研究人员提出假设，认为AD中能量代谢的下调是神经元在微环境中通过降低营养物质和供氧的等级来进行自我保护的一种特殊机制。进入AD后期，则正是这种较低等级的能量代谢和较高等级的调控和修复压力产生的矛盾，触发了细胞的凋亡。
这一新的假说对于AD致病机理的研究起到了积极的推动作用，为AD的药物设计也开辟了新的思路。(生物谷Bioon.com）
>>延伸阅读: JAD：科学家发现与老年痴呆症相关的新蛋白c-Abl
>>延伸阅读: 血管增生导致阿尔茨海默病
>>延伸阅读: Nature Cell Biology：阿尔茨海默氏症蛋白可能与朊病毒性质相似
doi:10.3233/JAD-2011-111313
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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.
