TY - JOUR
T1 - Differential Expression of Oxidative Phosphorylation Genes in Patients with Alzheimer's Disease
T2 - Implications for Early Mitochondrial Dysfunction and Oxidative Damage
AU - Manczak, Maria
AU - Park, Byung S.
AU - Jung, Youngsin
AU - Reddy, P. Hemachandra
N1 - Funding Information:
The authors thank the Harvard Tissue Resource Center, Belmont, MA (which is supported in part by PHS grant MH/NS 31862) for providing the brain specimens and the necessary pathological information. The authors also thank Geoffrey Murdoch, MD, Department of Pathology, OHSU for pathological interpretation of the brain specimens. This research was supported in part by the Alzheimer’s Association of Oregon, the Medical Research Foundation of Oregon, the American Federation for Aging Research, the Alzheimer’s Disease Center of Oregon, and NIA grants P30 AG08017, and AG22643. The authors thank Sandra Oster, PhD, Neurological Sciences Institute, Oregon Health & Science University, for critical reading of the manuscript.
PY - 2004
Y1 - 2004
N2 - In Alzheimer's disease (AD) pathogenesis, increasing evidence implicates mitochondrial dysfunction resulting from molecular defects in oxidative phosphorylation (OXPHOS). The objective of the present study was to determine the role of mRNA expression of mitochondrial genes responsible for OXPHOS in brain specimens from early AD and definite AD patients. In the present article, using quantitative real-time polymerase chain reaction (PCR) techniques, we studied mRNA expression of 11 mitochondrial-encoded genes in early AD patients (n = 6), definite AD patients (n = 6), and control subjects (n = 6). Using immunofluorescence techniques, we determined differentially expressed mitochondrial genes-NADH 15-kDa subunit (complex I), cytochrome oxidase subunit 1 (complex IV), and ATPase 8-subunit (complex V)-in the brain sections of AD patients and control subjects. Our quantitative reverse transcription (RT)-PCR analysis revealed a downregulation of mitochondrial genes in complex I of OXPHOS in both early and definite AD brain specimens. Further, the decrease of mRNA fold changes was higher for subunit 1 compared to all other subunits studied, suggesting that subunit 1 is critical for OXPHOS. Contrary to the downregulation of genes in complex I, complexes III and IV showed increased mRNA expressions in the brain specimens of both early and definite AD patients, suggesting a great demand on energy production. Further, mitochondrial gene expression varied greatly across AD patients, suggesting that mitochondrial DNA defects may be responsible for the heterogeneity of the phenotype in AD patients. Our immunofluorescence analyses of cytochrome oxidase and of the ATPase 8-subunit suggest that only subpopulations of neurons are differentially expressed in AD brains. Our double-labeling immunofluorescence analyses of 8-hydroxyguanosine and of cytochrome oxidase suggest that only selective, overexpressed neurons with cytochrome oxidase undergo oxidative damage in AD brains. Based on these results, we propose that an increase in cytochrome oxidase gene expression might be the result of functional compensation by the surviving neurons or an early mitochondrial alteration related to increased oxidative damage.
AB - In Alzheimer's disease (AD) pathogenesis, increasing evidence implicates mitochondrial dysfunction resulting from molecular defects in oxidative phosphorylation (OXPHOS). The objective of the present study was to determine the role of mRNA expression of mitochondrial genes responsible for OXPHOS in brain specimens from early AD and definite AD patients. In the present article, using quantitative real-time polymerase chain reaction (PCR) techniques, we studied mRNA expression of 11 mitochondrial-encoded genes in early AD patients (n = 6), definite AD patients (n = 6), and control subjects (n = 6). Using immunofluorescence techniques, we determined differentially expressed mitochondrial genes-NADH 15-kDa subunit (complex I), cytochrome oxidase subunit 1 (complex IV), and ATPase 8-subunit (complex V)-in the brain sections of AD patients and control subjects. Our quantitative reverse transcription (RT)-PCR analysis revealed a downregulation of mitochondrial genes in complex I of OXPHOS in both early and definite AD brain specimens. Further, the decrease of mRNA fold changes was higher for subunit 1 compared to all other subunits studied, suggesting that subunit 1 is critical for OXPHOS. Contrary to the downregulation of genes in complex I, complexes III and IV showed increased mRNA expressions in the brain specimens of both early and definite AD patients, suggesting a great demand on energy production. Further, mitochondrial gene expression varied greatly across AD patients, suggesting that mitochondrial DNA defects may be responsible for the heterogeneity of the phenotype in AD patients. Our immunofluorescence analyses of cytochrome oxidase and of the ATPase 8-subunit suggest that only subpopulations of neurons are differentially expressed in AD brains. Our double-labeling immunofluorescence analyses of 8-hydroxyguanosine and of cytochrome oxidase suggest that only selective, overexpressed neurons with cytochrome oxidase undergo oxidative damage in AD brains. Based on these results, we propose that an increase in cytochrome oxidase gene expression might be the result of functional compensation by the surviving neurons or an early mitochondrial alteration related to increased oxidative damage.
KW - 8-OHG
KW - Alzheimer's disease
KW - GAPDH
KW - Mitochondrial abnormalities
KW - Mitochondrial genes
KW - Oxidative damage
KW - Oxidative phosphorylation
KW - Postmortem brains
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U2 - 10.1385/NMM:5:2:147
DO - 10.1385/NMM:5:2:147
M3 - Article
C2 - 15075441
AN - SCOPUS:2342628596
SN - 1535-1084
VL - 5
SP - 147
EP - 162
JO - NeuroMolecular Medicine
JF - NeuroMolecular Medicine
IS - 2
ER -