NeuroMolecular Medicine

, Volume 5, Issue 2, pp 147–162 | Cite as

Differential expression of oxidative phosphorylation genes in patients with Alzheimer’s disease

Implications for early mitochondrial dysfunction and oxidative damage
  • Maria Manczak
  • Byung S. Park
  • Youngsin Jung
  • P. Hemachandra Reddy
Original Article

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 δ-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 δ-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, over-expressed 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.

Index Entries

Oxidative phosphorylation mitochondrial genes Alzheimer’s disease postmortem brains GAPDH mitochondrial abnormalities oxidative damage 8-OHG 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aarskog N. K. and Vedeler C. A. (2000) A new method that detects both the peripheral myelin protein 22 duplication in Charcot-Marie-Tooth type 1A disease and the peripheral myelin protein 22 deletion in hereditary neuropathy with liability to pressure palsies. Hum. Genet. 107, 494–498.PubMedCrossRefGoogle Scholar
  2. Aksenov M. Y., Tucker H. M., Nair P., et al. (1999) The expression of several mitochondrial and nuclear genes encoding the subunits of electron transport chain enzyme complexes, cytochrome c oxidase, NADH dehydrogenase in different brain regions in Alzheimer’s disease. Neurochem. Res. 24, 767–774.PubMedCrossRefGoogle Scholar
  3. Aldea C., Alvarez C. P., Folgueira L., Delgado R., and Otero J. R. (2002) Rapid detection of herpes simplex virus DNA in genital ulcers by real-time PCR suing SYBR green I dye as the detection signal. J. Clin. Microbiol. 40, 1060–1062.PubMedCrossRefGoogle Scholar
  4. Beal M. F. (1998) Mitochondrial dysfunction in neurodegenerative diseases. Biochim. Biophys. Acta 1366, 211–213.PubMedCrossRefGoogle Scholar
  5. Blass J. P. (1997) Cerebral metabolic impairments. In: Alzheimer’s disease:cause(s), diagnosis, treatment, and care. Khachuaturian Z. S. and Radebaugh T. S. (eds.). CRC Press NY, 1997;187–206.Google Scholar
  6. Blass J. P. (2000) The mitochondrial spiral. An adequate cause of dementia in Alzheimer’s disease. Ann. New Acad. Sci. 924, 170–183.CrossRefGoogle Scholar
  7. Blass J. P. (2001) Brain metabolism and brain disease: is metabolic deficiency the proximate cause of Alzheimer dementia? J. Neurosci. Res. 66, 851–856.PubMedCrossRefGoogle Scholar
  8. Bonilla E., Tanji K., Hirano M., Vu T. H., DiMauro S., and Schon E. A. (1999) Mitochondrial involvement in Alzheimer’s disease. Biochim. Biophys. Acta 1410, 171–182.PubMedCrossRefGoogle Scholar
  9. Bonilla E., Tanji K., Hirano M., Vu T. H., DiMauuro S., and Schon E. A. (2001) Mitochondrial involvement in Alzheimer’s disease. Biochim. Biophys. Acta: Bioenertics 1410, 171–182.CrossRefGoogle Scholar
  10. Braak H. and Braak E. (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 82, 239–259.PubMedCrossRefGoogle Scholar
  11. Bustin S. A. (2000) Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays. J. Mol. Endocrinol. 25, 169–193.PubMedCrossRefGoogle Scholar
  12. Castellano R., Hirai K., Aliev G., et al. (2002) Role of mitochondrial dysfunction in Alzheimer’s disease. J. Neurosci. Res. 70, 357–360.CrossRefGoogle Scholar
  13. Cavelier L., Erikson I., Tammi M., et al. (2001) Mt DNA mutations in maternally inherited diabetes: presence of the 3397NDI mutation previously associated with Alzheimer’s and Parkinson’s disease. Hereditas 135, 65–70.PubMedCrossRefGoogle Scholar
  14. Chandrasekaran K., Giordano T., Brady D. R., et al. (1994) Impairment in gene expression ox oxidative metabolism in vulnerable brain regions in Alzheimer’s disease. Neurobiol. Aging 14, 343–532.Google Scholar
  15. Chandrasekaran K., Hatanpää K., Brady D. R., and Rapoport S. I. (1996) Evidence for physiological down-regulation of brain oxidative phosphorylation in Alzheimer’s disease. Exp. Neurol. 142, 80–88.PubMedCrossRefGoogle Scholar
  16. Chandrasekaran K., Hatanpää K., Rapoport S. I., and Brady D. R. (1997) Decreased expression of nuclear and mitochdnrial DNA-encoded genes of oxidative phosphorylation in association neocortex in Alzheimer disease. Mol. Brain Res. 44, 99–104.PubMedCrossRefGoogle Scholar
  17. De la Monte S. M., Luong T. L., Neely T. R., Robinson D., and Wands J. R. (2000) Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer’s disease. Lab. Invest. 80, 1323–1335.PubMedCrossRefGoogle Scholar
  18. Egensperger R., Kosel S., Schnopp N. M., Mehraein P., and Graeber M. B. (1997) Association of the mitochondrial tRNA (A4336G) mutation with Alzheimer’s and Parkinson’s diseases. Neuropathol. Appl. Neurobiol. 23, 315–321.PubMedCrossRefGoogle Scholar
  19. Fukuyama R., Hatanpaa K., Rapoport S. I., and Chandrasekaran K. (1996) Gene expression of ND4, a subunit of complex I of oxidative phosphorylation in mitochondria, is deceased in temporal cortex of brains of Alzheimer’s disease patients. Brain Res. 25, 290–293.CrossRefGoogle Scholar
  20. Gutala R. V. and Reddy P. H. (2004) The use of real-time PCR analysis in a gene expression study of Alzheimer’s disease postmortem brain. J. Neurosci. Methods 131, 101–107.CrossRefGoogle Scholar
  21. Hatanpaa K., Chandrasekaran K., Brady D. R., and Rapoprt S. I. (1998) No association between Alzheimer’s plaques and decreased levels of cytochrome oxidase subunit mRNA, a marker of neuronal energy metabolism. Mol. Brain Res. 59, 13–21.PubMedCrossRefGoogle Scholar
  22. Hirai K., Aliev G., Nunomura A., et al. (2001) Mitochondrial abnormalities in Alzheimer’s disease. J. Neurosci. 21, 3017–3023.PubMedGoogle Scholar
  23. Hutchin T. P., Heath P. R., Pearson R. C., and Sinclair A. J. (1997) Mitochondrial DNA mutations in Alzheimer’s disease. Biochem. Biophys. Res. Commun. 241, 221–225.PubMedCrossRefGoogle Scholar
  24. Lin M. T., Simon D. K., Ahn C. H., Kim L. M., and Beal F. M. (2002) High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer’s disease brain. Hum. Mol. Genet. 11, 133–145.PubMedCrossRefGoogle Scholar
  25. Lin F. H., Lin R., Wisniewski H. M., Hwang Y. W., Grundke-Iqbal I., Healy-Louie G., and Iqbal K. (1992) Detection of point mutations in codon 331 of mitochondrial NADH dehydrogenase subunit 2 in Alzheimer’s brains. Biochem. Biophys. Res. Commun. 182, 238–246.PubMedCrossRefGoogle Scholar
  26. Mattson M. P., Pederson W. A., Duan W., Culmsee C., and Camandola S. (1999) Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer’s and Parkinson’s diseases. Ann NY Acad. Sci. 893, 154–175.PubMedCrossRefGoogle Scholar
  27. Ojaimi J. and Byrne E. (2001) Mitochondrial function and Alzheimer’s disease. Bio Signals Recept. 10, 254–262.CrossRefGoogle Scholar
  28. Olney R. C., Mougey E. B., Wang J., Shulman D. I., and Sylvester J. E. (2002) Using real-time, quantitative PCR for rapid genotyping of the steroid 21-hydroxylase gene in a north Florida population. J. Clin. Endocrinol. Metab. 87, 735–741.PubMedCrossRefGoogle Scholar
  29. Orth A. and Schpira A. H. V. (2001) Mitochondria and degenerative diseases. Am. J. Med. Genet. 106, 27–36.PubMedCrossRefGoogle Scholar
  30. Schapira A. H. (2002) Primary and secondary defects in the mitochondrial respiratory chain. J. Inherit. Meta-Dis. 25, 207–214.CrossRefGoogle Scholar
  31. Schapira A. H. V. and Cock H. R. (1999) Mitochondrial myopathies and encepahlomyopathies. Eur. J. Clin. Invest. 29, 886–898.PubMedCrossRefGoogle Scholar
  32. Shoffner J. M. (1997) Oxidative phosphorylation defects and Alzheimer’s disease. Neurogenetics 1, 13–19.PubMedCrossRefGoogle Scholar
  33. Schoffner J. M. (2000) Mitochondrial myopathy diagnosis. Neurol. Clin. 18, 105–123.CrossRefGoogle Scholar
  34. Shoffner J. M., Brown M. D., Torroni A., et al. (1993) Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients. Genomics 17, 171–184.PubMedCrossRefGoogle Scholar
  35. Sieber O. M., Lamlum H., Crabtree M. D., et al. (2002) Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or “multiple” colorectal adenomas. Proc. Natl. Acad. Sci. USA 99, 2954–2958.PubMedCrossRefGoogle Scholar
  36. Simonian N. A. and Hyman B. T. (1994) Functional alterations in Alzheimer’s disease: selective loss of mitochondrial-encoded cytochrome oxidase mRNA in the hippocampal formation. J. Neuropathol. Exp. Neurol. 53, 508–512.PubMedGoogle Scholar
  37. Strazielle C., Sturchler-Pierrat C., Staufenbiel M., and Lalonde R. (2003) Regional brain cytochrome oxidase activity in beta-amyloid precursor protein transgenic mice with the Swedish mutation. Neuroscience 118, 1151–1163.PubMedCrossRefGoogle Scholar
  38. User Bulletin no. 2 (1997) ABI Prism 7700 Sequence Detection System.Google Scholar
  39. Wallace D. C. (1999) Mitochondrial diseases in man and mouse. Science 283, 1482–1488.PubMedCrossRefGoogle Scholar
  40. Wallace D. C., Lott M. T., and Brown M. D. (1997) Mitochondrial defects in neurodegenerative diseases and aging. In Mitochondria and Free Radicals in Neurodegenerative Diseases. Beal F., Howell N., and Bodis-Wollner I., eds.). Wiley-Liss: NY, pp. 283–308.Google Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Maria Manczak
    • 1
  • Byung S. Park
    • 2
  • Youngsin Jung
    • 1
  • P. Hemachandra Reddy
    • 1
  1. 1.Neurogenetics Laboratory, Neurological Sciences InstituteOregon Health & Science UniversityBeaverton
  2. 2.Biostatistics and Bioinformatics CoreOregon Health & Science UniversityPortland

Personalised recommendations