CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
J Alzheimers Dis. 2012;28(2):389-402. doi: 10.3233/JAD-2011-111313.
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 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.
阿尔茨海默病（AD）领域的一个核心问题是将许多观察到的病理特征中的病因与后果区分开来，这可以通过研究这些特征在不同阶段的时间演变来解决。在这项工作中，对 AD 患者不同阶段死后脑组织转录组研究的综合分析揭示了 AD 进展过程中细胞机制的逐步崩溃。在 AD 的早期，淀粉样β寡聚体和淀粉样斑块的积累导致生物合成和能量代谢的下调。在中期，疾病的进展导致信号转导增强，而晚期则以凋亡增加为特征。AD 中能量代谢的下调被许多人认为是由于氧化应激导致线粒体损伤的结果。然而，氧化应激增强反应的不存在以及不同阶段电子传递链引人入胜的下调模式的揭示表明并非如此。与损伤主题假说相反，我们提出 AD 中能量代谢的下调是神经元对微环境中营养和氧气供应减少的一种保护反应。AD 晚期的凋亡增加是由低水平的能量代谢和高水平的调节和修复负担之间的冲突触发的。这一新假说对阿尔茨海默病的药物干预具有重要意义。
