title: Sporadic Alzheimer disease fibroblasts display an oxidative stress phenotype.
abstract: Alzheimer disease (AD) is a major health problem in the United States, affecting one in eight Americans over the age of 65. The number of elderly suffering from AD is expected to continue to increase over the next decade, as the average age of the U.S. population increases. The risk factors for and etiology of AD are not well understood; however, recent studies suggest that exposure to oxidative stress may be a contributing factor. Here, microarray gene expression signatures were compared in AD-patient-derived fibroblasts and normal fibroblasts exposed to hydrogen peroxide or menadione (to simulate conditions of oxidative stress). Using the 23K Illumina cDNA microarray to screen expression of >14,000 human genes, we identified a total of 1017 genes that are chronically up- or downregulated in AD fibroblasts, 215 of which were also differentially expressed in normal human fibroblasts within 12h after exposure to hydrogen peroxide or menadione. Pathway analysis of these 215 genes and their associated pathways revealed cellular functions that may be critically dysregulated by oxidative stress and play a critical role in the etiology and/or pathology of AD. We then examined the AD fibroblasts for the presence of oxidative DNA damage and found increased accumulation of 8-oxo-guanine. These results indicate the possible role of oxidative stress in the gene expression profile seen in AD.
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, 251 Bayview Boulevard, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Ramamoorthy
authors.forename: Peter
authors.initials: P
authors.lastname: Sykora
authors.forename: Morten
authors.initials: M
authors.lastname: Scheibye-Knudsen
authors.forename: Christopher
authors.initials: C
authors.lastname: Dunn
authors.forename: Cindy
authors.initials: C
authors.lastname: Kasmer
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D004249:DNA Damage; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053858:Metabolic Networks and Pathways / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D010641:Phenotype; D014158:Transcription, Genetic; D059467:Transcriptome; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: D016877:Oxidants; D024483:Vitamin K 3; D006861:Hydrogen Peroxide