Differential Expression of Oxidative Phosphorylation Genes in Patients with Alzheimer's Disease: Implications for Early Mitochondrial Dysfunction and Oxidative Damage

Maria Manczak, Byung Park, Youngsin Jung, P (Hemachandra) Reddy

Research output: Contribution to journalArticle

220 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)147-162
Number of pages16
JournalNeuroMolecular Medicine
Volume5
Issue number2
DOIs
StatePublished - 2004

Fingerprint

Oxidative Phosphorylation
Alzheimer Disease
Mitochondrial Genes
Electron Transport Complex IV
Genes
Brain
Fluorescent Antibody Technique
Messenger RNA
Neurons
Adenosine Triphosphatases
Down-Regulation
Gene Expression
Electron Transport Complex III
Mitochondrial DNA
NAD
Reverse Transcription
Real-Time Polymerase Chain Reaction
Phenotype
Polymerase Chain Reaction

Keywords

  • 8-OHG
  • Alzheimer's disease
  • GAPDH
  • Mitochondrial abnormalities
  • Mitochondrial genes
  • Oxidative damage
  • Oxidative phosphorylation
  • Postmortem brains

ASJC Scopus subject areas

  • Neuroscience(all)
  • Genetics
  • Cell Biology

Cite this

Differential Expression of Oxidative Phosphorylation Genes in Patients with Alzheimer's Disease : Implications for Early Mitochondrial Dysfunction and Oxidative Damage. / Manczak, Maria; Park, Byung; Jung, Youngsin; Reddy, P (Hemachandra).

In: NeuroMolecular Medicine, Vol. 5, No. 2, 2004, p. 147-162.

Research output: Contribution to journalArticle

@article{04f3b45eccee46859b03d105376c2855,
title = "Differential Expression of Oxidative Phosphorylation Genes in Patients with Alzheimer's Disease: Implications for Early Mitochondrial Dysfunction and Oxidative Damage",
abstract = "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.",
keywords = "8-OHG, Alzheimer's disease, GAPDH, Mitochondrial abnormalities, Mitochondrial genes, Oxidative damage, Oxidative phosphorylation, Postmortem brains",
author = "Maria Manczak and Byung Park and Youngsin Jung and Reddy, {P (Hemachandra)}",
year = "2004",
doi = "10.1385/NMM:5:2:147",
language = "English (US)",
volume = "5",
pages = "147--162",
journal = "NeuroMolecular Medicine",
issn = "1535-1084",
publisher = "Humana Press",
number = "2",

}

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

AU - Jung, Youngsin

AU - Reddy, P (Hemachandra)

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

UR - http://www.scopus.com/inward/record.url?scp=2342628596&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2342628596&partnerID=8YFLogxK

U2 - 10.1385/NMM:5:2:147

DO - 10.1385/NMM:5:2:147

M3 - Article

C2 - 15075441

AN - SCOPUS:2342628596

VL - 5

SP - 147

EP - 162

JO - NeuroMolecular Medicine

JF - NeuroMolecular Medicine

SN - 1535-1084

IS - 2

ER -