Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer's disease

作者：Koen Bossers, Kerstin T.S. Wirz, Gideon F. Meerhoff, Anke H. W. Essing, Jeroen W. van Dongen, Pieter H.J. Houba, Chris Gerrit Kruse, Joost Verhaagen, Dick Frans Swaab · 发表于：Brain · 年份：2010 · DOI：10.1093/brain/awq258 · 被引用次数：237 · 研究领域：Alzheimer's disease research and treatments、Bioinformatics and Genomic Networks、Cholinesterase and Neurodegenerative Diseases

Using the Braak staging for neurofibrillary changes as an objective indicator of the progression of Alzheimer's disease, we have performed a systematic search for global gene expression changes in the prefrontal cortex during the course of Alzheimer's disease. In the prefrontal cortex, senile plaques and neurofibrillary changes start to appear around Braak stage III, allowing for the detection of changes in gene expression before, during and after the onset of Alzheimer's disease neuropathology. Two distinct patterns of tightly co-regulated groups of genes were observed: (i) an increase in expression in early Braak stages, followed by a decline in expression in later stages (the UPDOWN clusters; containing 865 genes) and (ii) a decrease in expression in early Braak stages, followed by an increase in expression in later stages (the DOWNUP clusters; containing 983 genes). The most profound changes in gene expression were detected between Braak stages II and III, just before or at the onset of plaque pathology and neurofibrillary changes in the prefrontal cortex. We also observed an increase in intracellular beta amyloid staining from Braak stages I to III and a clear decrease in Braak stages IV to VI. These data suggest a link between specific gene expression clusters and Alzheimer's disease-associated neuropathology in the prefrontal cortex. Gene ontology over-representation and functional gene network analyses indicate an increase in synaptic activity and changes in plasticit...