Analysis of 1184 gene transcript levels in Alzheimer CA1 hippocampus: synaptic signaling and transcription factor deficits and upregulation of pro-inflammatory pathways

Deregulation of brain transcription, translation and protein processing are a consistent and recurrent theme in Alzheimer's disease (AD), suggesting c hanges in diverse aspects of brain gene expression. To further understand a lterations in sporadicAD gene transcription, 1184 mRNA levels were analyzed in broad-spectrum cDNA array panels probed with hippocampal CA1 mRNA isola ted from 10 AD and control brains. There were no significant differences in drug history, age (69.2+/-1.5 vs. 68.8+/-1.9 yr, p=0.75) or post-mortem in terval (2.1+/-0.7 vs, 2.0+/-0.7 hr, p=0.93), AD vs control, between each of the two brain groups. None of the AD brains sampled had a known history of genetic brain disease. We report here that of the 22 strongest signal diff erences detected, including 19 mRNA species hitherto unreported, AD-affecte d hippocampal CA1 showed statistically significant decreases (p less than o r equal to 0.05) in the intensity of reporter signals for 11 genes encoding transcription factors and signal transduction elements involved in synapti c organization. These defects correlate well with the generalized down-regu lation of gene expression in AD brain and with deficiencies in genes encodi ng elements essential for synaptic transmission. Increases in 6 potentially pro-inflammatory transcripts were strikingly apparent; these increases ind icate that at the genetic level, RNA signals encoding highly reactive pro-i nflammatory elements are abundant in terminal AD hippocampal CA1.