Skip to main content
NCBI home page
American Journal of Alzheimer's Disease and Other Dementias logoLink to American Journal of Alzheimer's Disease and Other Dementias
. 2004 Nov-Dec;19(6):345–352. doi: 10.1177/153331750401900611

Mitochondrial failures in Alzheimer's disease

Xiongwei Zhu, Mark A Smith 1, George Perry, Gjumrakch Aliev 2
PMCID: PMC10834012  PMID: 15633943

Abstract

Mitochondrial dysfunction and free radical-induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases such as Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Alzheimer's disease (AD). The defective adenosine triphosphate (ATP) production and increased oxygen radicals may induce mitochondria-dependent cell death because damaged mitochondria are unable to maintain the energy demands of the cell. The role of vascular hypoperfusion-induced mitochondria failure in the pathogenesis of AD now has been widely accepted. However, the exact cellular mechanisms behind vascular lesions and their relation to oxidative stress markers identified by RNA oxidation, lipid peroxidation, or mitochondrial DNA (mt DNA) deletion remain unknown. Future studies comparing the spectrum of mitochondrial damage and the relationship to oxidative stress-induced damage during the aging process or, more importantly, during the maturation of AD pathology are warranted.

Keywords: mitochondria, Alzheimer's disease, hypoperfusion, mitochondrial DNA deletion, amyloid cascade

Full Text

The Full Text of this article is available as a PDF (9.2 MB).

Contributor Information

Mark A. Smith, Institute of Pathology, Case Western Reserve University, Cleveland, Ohio..

Gjumrakch Aliev, Departments of Pathology and the Microscopy Research Center, Case Western Reserve University, Cleveland, Ohio..

References

  1. Cadenas E, Davies KJ: Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med.2000; 29(3-4): 222-230. [DOI] [PubMed] [Google Scholar]
  2. Kidd PM, LeVine SM: The biochemistry of free radicals. In Kidd PM, LeVine SM (eds.): Antioxidant Adaptation: Its Role in Free Radical Pathology.San Leandro, CA: Allergy Research Group, 1986. [Google Scholar]
  3. Kidd PM, Huber W, Summerfield F (eds.): Coenzyme Q10: Essential Energy Carrier and Antioxidant.Berkeley, CA: H.K. Biomedical Consultants, 1988. [Google Scholar]
  4. Castellani R, Hirai K, Aliev G, et al.: Role of mitochondrial dysfunction in Alzheimer's disease. J Neurosci Res.2002; 70(3): 357-360. [DOI] [PubMed] [Google Scholar]
  5. Gibson GE, Sheu KF, Blass JP: Abnormalities of mitochondrial enzymes in Alzheimer disease. J Neural Transm.1998; 105(8-9): 855-870. [DOI] [PubMed] [Google Scholar]
  6. Chandrasekaran K, Giordano T, Brady DR, et al.: Impairment in mitochondrial cytochrome oxidase gene expression in Alzheimer disease. Brain Res Mol Brain Res.1994; 24(1-4): 336-340. [DOI] [PubMed] [Google Scholar]
  7. Cottrell DA, Blakely EL, Johnson MA, et al.: Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD. Neurology.2001; 57(2): 260-264. [DOI] [PubMed] [Google Scholar]
  8. Maurer I, Zierz S, Moller HJ: A selective defect of cytochrome-c oxidase is present in brain of Alzheimer disease patients. Neurobiol Aging.2000; 21(3): 455-462. [DOI] [PubMed] [Google Scholar]
  9. Nagy Z, Esiri MM, LeGris M, et al.: Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology. Acta Neuropathol (Berl).1999; 97(4): 346-354. [DOI] [PubMed] [Google Scholar]
  10. Parker WD Jr, Mahr NJ, Filley CM, et al.: Reduced platelet cytochrome-c oxidase activity in Alzheimer's disease. Neurology. 1994; 44(6): 1086-1090. [DOI] [PubMed] [Google Scholar]
  11. Parker WD Jr, Parks J, Filley CM, et al.: Electron transport chain defects in Alzheimer's disease brain. Neurology.1994; 44(6): 1090-1096. [DOI] [PubMed] [Google Scholar]
  12. Gibson GE, Haroutunian V, Zhang H, et al.: Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype. Ann Neurol.2000; 48(3): 297-303. [PubMed] [Google Scholar]
  13. Davis RE, Miller S, Herrnstadt C, et al.: Mutations in mitochondrial cytochrome-c oxidase genes segregate with late-onset Alzheimer disease. Proc Natl Acad Sci USA.1997; 94(9): 4526-4531. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  14. Swerdlow RH, Parks JK, Cassarino DS, et al.: Cybrids in Alzheimer's disease: A cellular model of the disease? Neurology. 1997; 49(4): 918-925. [DOI] [PubMed] [Google Scholar]
  15. Hirai K, Aliev G, Nunomura A, et al.: Mitochondrial abnormalities in Alzheimer's disease. J Neurosci.2001; 21(9): 3017-3023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mecocci P, MacGarvey U, Kaufman AE, et al.: Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann Neurol.1993; 34(4): 609-616. [DOI] [PubMed] [Google Scholar]
  17. Mecocci P, MacGarvey U, Beal MF: Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann Neurol. 1994; 36(5): 747-751. [DOI] [PubMed] [Google Scholar]
  18. Mecocci P, Beal MF, Cecchetti R, et al.: Mitochondrial membrane fluidity and oxidative damage to mitochondrial DNA in aged and AD human brain. Mol Chem Neuropathol.1997; 31(1): 53-64. [DOI] [PubMed] [Google Scholar]
  19. Mecocci P, Polidori MC, Ingegni T, et al.: Oxidative damage to DNA in lymphocytes from AD patients. Neurology.1998; 51(4): 1014-1017. [DOI] [PubMed] [Google Scholar]
  20. Coskun PE, Beal MF, Wallace DC: Alzheimer's brains harbor somatic mt DNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci USA.2004; 101(29): 10726-10731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Blass JP: The mitochondrial spiral. An adequate cause of dementia in the Alzheimer's syndrome. Ann N Y Acad Sci.2000; 924: 170-183. [DOI] [PubMed] [Google Scholar]
  22. Baloyannis SJ, Costa V, Michmizos D: Mitochondrial alterations in Alzheimer's disease. Am J Alzheimers Dis Other Demen.2004; 19(2): 89-93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Minoshima S, Giordani B, Berent S, et al.: Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease. Ann Neurol.1997; 42(1): 85-94. [DOI] [PubMed] [Google Scholar]
  24. Fukuyama H, Ogawa M, Yamauchi H, et al.: Altered cerebral energy metabolism in Alzheimer's disease: A PET study. J Nucl Med.1994; 35(1): 1-6. [PubMed] [Google Scholar]
  25. Hoyer S: Intermediary metabolism disturbance in AD/SDAT and its relation to molecular events. Prog Neuropsychopharmacol Biol Psychiatry.1993; 17(2): 199-228. [DOI] [PubMed] [Google Scholar]
  26. Blass JP, Gibson GE: Cerebrometabolic aspects of delirium in relationship to dementia. Dement Geriatr Cogn Disord.1999; 10(5): 335-338. [DOI] [PubMed] [Google Scholar]
  27. Coyle JT, Puttfarcken P: Oxidative stress, glutamate, and neurodegenerative disorders. Science.1993; 262(5134): 689-695. [DOI] [PubMed] [Google Scholar]
  28. Zhu X, Raina AK, Lee HG, et al.: Oxidative stress signalling in Alzheimer's disease. Brain Res.2004; 1000(1-2): 32-39. [DOI] [PubMed] [Google Scholar]
  29. Serra JA, Dominguez RO, de Lustig ES, et al.: Parkinson's disease is associated with oxidative stress: Comparison of peripheral antioxidant profiles in living Parkinson's, Alzheimer's and vascular dementia patients. J Neural Transm.2001; 108(10): 1135-1148. [DOI] [PubMed] [Google Scholar]
  30. Gsell W, Conrad R, Hickethier M, et al.: Decreased catalase activity but unchanged superoxide dismutase activity in brains of patients with dementia of Alzheimer type. J Neurochem.1995; 64(3): 1216-1223. [DOI] [PubMed] [Google Scholar]
  31. Kumar A, Schapiro MB, Haxby JV, et al.: Cerebral metabolic and cognitive studies in dementia with frontal lobe behavioral features. J Psychiatr Res.1990; 24(2): 97-109. [DOI] [PubMed] [Google Scholar]
  32. Friston KJ, Frackowiak RS: Cerebral function in aging and Alzheimer's disease: The role of PET. Electroencephalogr Clin Neurophysiol Suppl.1991; 42: 355-365. [PubMed] [Google Scholar]
  33. De Jong GI, De Vos RA, Steur EN, et al.: Cerebrovascular hypoperfusion: A risk factor for Alzheimer's disease? Animal model and postmortem human studies. Ann N Y Acad Sci.1997; 826: 56-74. [DOI] [PubMed] [Google Scholar]
  34. de la Torre JC: Cerebromicrovascular pathology in Alzheimer's disease compared to normal aging. Gerontology.1997; 43(1-2): 26-43. [DOI] [PubMed] [Google Scholar]
  35. de la Torre JC: Hemodynamic consequences of deformed microvessels in the brain in Alzheimer's disease. Ann N Y Acad Sci. 1997; 826: 75-91. [DOI] [PubMed] [Google Scholar]
  36. de la Torre JC: Alzheimer disease as a vascular disorder: Nosological evidence. Stroke.2002; 33(4): 1152-1162. [DOI] [PubMed] [Google Scholar]
  37. Galle J, Stunz P, Schollmeyer P, et al.: Oxidized LDL and lipoprotein(a) stimulate renin release of juxtaglomerular cells. Kidney Int. 1995; 47(1): 45-52. [DOI] [PubMed] [Google Scholar]
  38. Lipton P: Ischemic cell death in brain neurons. Physiol Rev.1999; 79(4): 1431-1568. [DOI] [PubMed] [Google Scholar]
  39. Sekhon LH, Morgan MK, Spence I, et al.: Chronic cerebral hypoperfusion: Pathological and behavioral consequences. Neurosurgery.1997; 40(3): 548-556. [DOI] [PubMed] [Google Scholar]
  40. de la Torre JC: Critically attained threshold of cerebral hypoperfusion: The CATCH hypothesis of Alzheimer's pathogenesis. Neurobiol Aging.2000; 21(2): 331-342. [DOI] [PubMed] [Google Scholar]
  41. Anandatheerthavarada HK, Biswas G, Robin MA, et al.: Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol.2003; 161(1): 41-54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Askanas V, McFerrin J, Baque S, et al.: Transfer of beta-amyloid precursor protein gene using adenovirus vector causes mitochondrial abnormalities in cultured normal human muscle. Proc Natl Acad Sci USA.1996; 93(3): 1314-1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Grant SM, Shankar SL, Chalmers-Redman RM, et al.: Mitochondrial abnormalities in neuroectodermal cells stably expressing human amyloid precursor protein (hAPP751). Neuroreport.1999; 10(1): 41-46. [DOI] [PubMed] [Google Scholar]
  44. Casley CS, Canevari L, Land JM, et al.: Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J Neurochem.2002; 80(1): 91-100. [DOI] [PubMed] [Google Scholar]
  45. Moreira PI, Santos MS, Moreno A, et al.: Effect of amyloid betapeptide on permeability transition pore: A comparative study. J Neurosci Res.2002; 69(2): 257-267. [DOI] [PubMed] [Google Scholar]
  46. Gibson GE, Park LC, Sheu KF, et al.: The alpha-ketoglutarate dehydrogenase complex in neurodegeneration. Neurochem Int.2000; 36(2): 97-112. [DOI] [PubMed] [Google Scholar]
  47. Kish SJ: Brain energy metabolizing enzymes in Alzheimer's disease: Alpha-ketoglutarate dehydrogenase complex and cytochrome oxidase. Ann N Y Acad Sci.1997; 826: 218-228. [DOI] [PubMed] [Google Scholar]
  48. Lustbader JW, Cirilli M, Lin C, et al.: ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science.2004; 304(5669): 448-452. [DOI] [PubMed] [Google Scholar]
  49. Aliev G, Seyidova D, Neal ML, et al.: Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice. Ann N Y Acad Sci.2002; 977: 45-64. [DOI] [PubMed] [Google Scholar]
  50. Orth M, Schapira AH: Mitochondria and degenerative disorders. Am J Med Genet.2001; 106(1): 27-36. [DOI] [PubMed] [Google Scholar]
  51. Schapira AH: Oxidative stress and mitochondrial dysfunction in neurodegeneration. Curr Opin Neurol.1996; 9(4): 260-264. [DOI] [PubMed] [Google Scholar]
  52. Schon EA, Bonilla E, DiMauro S: Mitochondrial DNA mutations and pathogenesis. J Bioenerg Biomembr.1997; 29(2): 131-149. [DOI] [PubMed] [Google Scholar]
  53. Corral-Debrinski M, Horton T, Lott MT, et al.: Marked changes in mitochondrial DNA deletion levels in Alzheimer brains. Genomics. 1994; 23(2): 471-476. [DOI] [PubMed] [Google Scholar]
  54. Hutchin T, Cortopassi G: A mitochondrial DNA clone is associated with increased risk for Alzheimer disease. Proc Natl Acad Sci USA.1995; 92(15): 6892-6895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Shoffner JM, Brown MD, Torroni A, et al.: Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients. Genomics.1993; 17(1): 171-184. [DOI] [PubMed] [Google Scholar]
  56. Egensperger R, Kosel S, Schnopp NM, et al.: Association of the mitochondrial tRNA(A4336G) mutation with Alzheimer's and Parkinson's diseases. Neuropathol Appl Neurobiol.1997; 23(4): 315-321. [PubMed] [Google Scholar]
  57. Wragg MA, Talbot CJ, Morris JC, et al.: No association found between Alzheimer's disease and a mitochondrial tRNA glutamine gene variant. Neurosci Lett.1995; 201(2): 107-110. [DOI] [PubMed] [Google Scholar]
  58. Arbuzova S, Hutchin T, Cuckle H: Mitochondrial dysfunction and Down's syndrome. Bioessays.2002; 24(8): 681-684. [DOI] [PubMed] [Google Scholar]
  59. Mudd SH, Levy HL, Kraus JP: Disorders of transsulfuration. In Scriver CR, Beaudet AL, Sly WS, et al. (eds.): The Metabolic and Molecular Bases of Inherited Disease. 8th Edition.New York: McGraw-Hill, 2001: 2007-2056. [Google Scholar]
  60. Eto K, Asada T, Arima K, et al.: Brain hydrogen sulfide is severely decreased in Alzheimer's disease. Biochem Biophys Res Commun. 2002; 293(5): 1485-1488. [DOI] [PubMed] [Google Scholar]
  61. Seshadri S, Beiser A, Selhub J, et al.: Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002; 346(7): 476-483. [DOI] [PubMed] [Google Scholar]
  62. Austin RC, Sood SK, Dorward AM, et al.: Homocysteine-dependent alterations in mitochondrial gene expression, function and structure. Homocysteine and H2O2 act synergistically to enhance mitochondrial damage. J Biol Chem.1998; 273(46): 30808-30817. [DOI] [PubMed] [Google Scholar]
  63. Streck EL, Vieira PS, Wannmacher CM, et al.: In vitro effect of homocysteine on some parameters of oxidative stress in rat hippocampus. Metab Brain Dis.2003; 18(2): 147-154. [DOI] [PubMed] [Google Scholar]
  64. Streck EL, Delwing D, Tagliari B, et al.: Brain energy metabolism is compromised by the metabolites accumulating in homocystinuria. Neurochem Int.2003; 43(6): 597-602. [DOI] [PubMed] [Google Scholar]
  65. Streck EL, Matte C, Vieira PS, et al.: Impairment of energy metabolism in hippocampus of rats subjected to chemically-induced hyperhomocysteinemia. Biochim Biophys Acta.2003; 1637(3): 187-192. [DOI] [PubMed] [Google Scholar]
  66. Kim JM, Lee H, Chang N: Hyperhomocysteinemia due to shortterm folate deprivation is related to electron microscopic changes in the rat brain. J Nutr.2002; 132(11): 3418-3421. [DOI] [PubMed] [Google Scholar]
  67. Chang L, Xu JX, Zhao J, et al.: Taurine antagonized oxidative stress injury induced by homocysteine in rat vascular smooth muscle cells. Acta Pharmacol Sin.2004; 25(3): 341-346. [PubMed] [Google Scholar]
  68. Chang L, Zhao J, Xu J, et al.: Effects of taurine and homocysteine on calcium homeostasis and hydrogen peroxide and superoxide anions in rat myocardial mitochondria. Clin Exp Pharmacol Physiol. 2004; 31(4): 237-243. [DOI] [PubMed] [Google Scholar]
  69. Robert K, Chasse JF, Santiard-Baron D, et al.: Altered gene expression in liver from a murine model of hyperhomocysteinemia. J Biol Chem.2003; 278(34): 31504-31511. [DOI] [PubMed] [Google Scholar]
  70. Nunomura A, Perry G, Pappolla MA, et al.: Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome. J Neuropathol Exp Neurol.2000; 59(11): 1011-1017. [DOI] [PubMed] [Google Scholar]
  71. Nunomura A, Perry G, Aliev G, et al.: Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol.2001; 60(8): 759-767. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Alzheimer's Disease and Other Dementias are provided here courtesy of SAGE Publications

RESOURCES