Affiliations: [a] CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China | [b] Graduate University, Chinese Academy of Sciences, Beijing, China | [c] UC Davis Genome Center and Department of Biomedical Engineering, Davis, CA, USA | [d] College of Physics, Huazhong University of Science and Technology, Wuhan, China
Correspondence:
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Correspondence to: Hongxing Lei, Beijing Institute of Genomics, No.7 Beitucheng west Road, Chaoyang district, Beijing 100029, China; Tel/Fax: +086 10 82995396; E-mail: leihx@big.ac.cn and Yong Duan, Tel.: +001 530 7547632; Fax: +001 530 7549658; E-mail: duan@ucdavis.edu.
Note: [1] These authors contributed equally.
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 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.
Keywords: Brain tissue, microarray, signal transduction, neuronal cell death
