Human Molecular Genetics Advance Access originally published online on April 28, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 12 1225-1240
DOI: 10.1093/hmg/ddh140
Human Molecular Genetics, Vol. 13, No. 12 © Oxford University Press 2004; all rights reserved
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
1Neurogenetics Laboratory, Neurological Sciences Institute, 2Spotted Microarray Core, Gene Microarray Shared Resource, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA, 3Bioinformatics and Biostatistics Core, Gene Microarray Shared Resource, 4Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA, 5Department of Neurology, Portland Veteran's Affairs Medical Center and 6Department of Neurology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201, USA
Received January 23, 2004; Accepted April 15, 2004
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the impairment of cognitive functions and by beta amyloid (Aß) 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 Aß 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 Aß, and that the up-regulation of mitochondrial genes is a compensatory response. These findings have important implications for understanding the mechanism of Aß toxicity in AD and for developing therapeutic strategies for AD.
* To whom correspondence should be addressed at: Neurogenetics Laboratory, Neurological Sciences Institute, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA. Tel: +1 5034182625; Fax: +1 5034182501; Email: reddyh{at}ohsu.edu
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