Journal Article

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

P. Hemachandra Reddy, Shannon McWeeney, Byung S. Park, Maria Manczak, Ramana V. Gutala, Dara Partovi, Youngsin Jung, Vincent Yau, Robert Searles, Motomi Mori and Joseph Quinn

in Human Molecular Genetics

Volume 13, issue 12, pages 1225-1240
Published in print June 2004 | ISSN: 0964-6906
Published online April 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh140
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

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Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the impairment of cognitive functions and by beta amyloid (Aβ) 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 Aβ 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 Aβ, and that the up-regulation of mitochondrial genes is a compensatory response. These findings have important implications for understanding the mechanism of Aβ toxicity in AD and for developing therapeutic strategies for AD.

Journal Article.  10101 words.  Illustrated.

Subjects: Genetics and Genomics

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