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
Language: 
English
Short Title: 
Gene expression profiles of transcripts in amyloid precursor protein transgenic mice
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.

Author(s): 
Reddy, P. Hemachandra
McWeeney, Shannon
Park, Byung S.
Manczak, Maria
Gutala, Ramana V.
Partovi, Dara
Jung, Youngsin
Yau, Vincent
Searles, Robert
Mori, Motomi
Quinn, Joseph
Item Type: 
Journal Article
Publication Title: 
Human Molecular Genetics
Journal Abbreviation: 
Hum. Mol. Genet.
Publication Date: 
Jun 15, 2004
Publication Year: 
2004
Pages: 
1225-1240
Volume: 
13
Issue: 
12
ISSN: 
0964-6906
DOI: 
10.1093/hmg/ddh140
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 15115763

Turabian/Chicago Citation

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. Jun 15, 2004. "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." Human Molecular Genetics 13: 12: 1225-1240. 10.1093/hmg/ddh140.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1093/hmg/ddh140 | issn = 0964-6906 | volume = 13 | pages = 1225-1240 | last = Reddy | first = P. Hemachandra | coauthors = McWeeney, Shannon, Park, Byung S., Manczak, Maria, Gutala, Ramana V., Partovi, Dara, Jung, Youngsin, Yau, Vincent, Searles, Robert, Mori, Motomi, Quinn, Joseph | 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 | journal = Human Molecular Genetics | date = Jun 15, 2004 | pmid = | pmc = }} </ref>