title: Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the impairment of cognitive functions and by beta amyloid (Abeta) plaques in the cerebral cortex and the hippocampus. Our objective was to determine genes that are critical for cellular changes in AD progression, with particular emphasis on changes early in disease progression. We investigated an established amyloid precursor protein (APP) transgenic mouse model (the Tg2576 mouse model) for gene expression profiles at three stages of disease progression: long before (2 months of age), immediately before (5 months) and after (18 months) the appearance of Abeta plaques. Using cDNA microarray techniques, we measured mRNA levels in 11 283 cDNA clones from the cerebral cortex of Tg2576 mice and age-matched wild-type (WT) mice at each of the three time points. This gene expression analysis revealed that the genes related to mitochondrial energy metabolism and apoptosis were up-regulated in 2-month-old Tg2576 mice and that the same genes were up-regulated at 5 and 18 months of age. These microarray results were confirmed using northern blot analysis. Results from in situ hybridization of mitochondrial genes-ATPase-6, heat-shock protein 86 and programmed cell death gene 8-suggest that the granule cells of the hippocampal dentate gyrus and the pyramidal neurons in the hippocampus and the cerebral cortex are up-regulated in Tg2576 mice compared with WT mice. Results from double-labeling in situ hybridization suggest that in Tg2576 mice only selective, over-expressed neurons with the mitochondrial gene ATPase-6 undergo oxidative damage. These results, therefore, suggest that mitochondrial energy metabolism is impaired by the expression of mutant APP and/or Abeta, and that the up-regulation of mitochondrial genes is a compensatory response. These findings have important implications for understanding the mechanism of Abeta toxicity in AD and for developing therapeutic strategies for AD.
authors.affiliation: Neurogenetics Laboratory, Neurological Sciences Institute, Oregon Health and Science University, Beaverton, OR 97006, USA. reddyh@ohsu.edu
authors.forename: P Hemachandra
authors.initials: PH
authors.lastname: Reddy
authors.forename: Shannon
authors.initials: S
authors.lastname: McWeeney
authors.forename: Byung S
authors.initials: BS
authors.lastname: Park
authors.forename: Maria
authors.initials: M
authors.lastname: Manczak
authors.forename: Ramana V
authors.initials: RV
authors.lastname: Gutala
authors.forename: Dara
authors.initials: D
authors.lastname: Partovi
authors.forename: Youngsin
authors.initials: Y
authors.lastname: Jung
authors.forename: Vincent
authors.initials: V
authors.lastname: Yau
authors.forename: Robert
authors.initials: R
authors.lastname: Searles
authors.forename: Motomi
authors.initials: M
authors.lastname: Mori
authors.forename: Joseph
authors.initials: J
authors.lastname: Quinn
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006360:Heat-Shock Proteins / Q000235:genetics; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010086:Oxidative Phosphorylation Coupling Factors / Q000378:metabolism; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D016564:Amyloid beta-Protein Precursor; D006360:Heat-Shock Proteins; D010086:Oxidative Phosphorylation Coupling Factors; D012333:RNA, Messenger; C002992:8-hydroxyadenine; C000628217:F(6) ATPase; D025261:Mitochondrial Proton-Translocating ATPases; D000225:Adenine