Clinical Features and Pathogenesis of Alzheimer’s Disease: Involvement of Mitochondria and Mitochondrial DNA

  • Michelangelo Mancuso
  • Daniele Orsucci
  • Annalisa LoGerfo
  • Valeria Calsolaro
  • Gabriele Siciliano
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 685)


Alzheimer’s disease (AD) is a neurodegenerative disorder which results in the irreversible loss of cortical neurons, particularly in the associative neocortex and hippocampus. AD is the most common form of dementia in the elderly people. Apart from the neuronal loss, the pathological hallmarks are extracellular senile plaques containing the peptide beta-amyloid (Aβ) and neurofibrillary tangles. The Aβ cascade hypothesis remains the main pathogenetic model, as suggested by familiar AD, mainly associated to mutation in amyloid precursor protein and presenilin genes. The remaining 95% of AD patients are mostly sporadic late-onset cases, with a complex aetiology due to interactions between environmental conditions and genetic features of the individual.

Mitochondria play a central role in the bioenergetics of the cell and apoptotic cell death. Morphological, biochemical and genetic abnormalities of the mitochondria in several AD tissues have been reported. Impaired mitochondrial respiration, particularly COX deficiency, has been observed in brain, platelets and fibroblasts of AD patients. Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure and increased oxidative stress. No causative mutations in the mtDNA have been detected and studies on mtDNA polymorphisms are controversial, but the “mitochondrial cascade hypothesis”, here revised, could explain many of the biochemical, genetic and pathological features of spora


Mild Cognitive Impairment Electron Transport Chain Mild Cognitive Impairment Patient Neurobiol Aging Cybrid Cell 


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  1. 1.
    Blenno K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet 2006; 368:387–403.CrossRefGoogle Scholar
  2. 2.
    Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002; 297:353–356.CrossRefPubMedGoogle Scholar
  3. 3.
    Riedl V, Honey CJ. Alzheimer’s disease: a search for broken links. J Neurosci 2008; 28:8148–8149.CrossRefPubMedGoogle Scholar
  4. 4.
    Jellinger KA, Janetzky B, Attems J et al. Biomarkers for early diagnosis of Alzheimer disease: ‘ALZheimer ASsociated gene’—a new blood biomarker? J Cell Mol Med 2008; 2:1094–1117.CrossRefGoogle Scholar
  5. 5.
    Gauthier S, Reisberg B, Zaudig M et al. Mild cognitive impairment. Lancet 2006; 367:1262–1270.CrossRefPubMedGoogle Scholar
  6. 6.
    Ray S, Britschgi M, Herbert C et al. Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat Med 2007; 13:1359–1362.CrossRefPubMedGoogle Scholar
  7. 7.
    Goedert M, Spillantini MG. A Century of Alzheimer’s Disease. Science 2006; 314:777–781.CrossRefPubMedGoogle Scholar
  8. 8.
    Blass JP, Sheu RK, Gibson GE. Inherent abnormalities in energy metabolism in Alzheimer disease. Interaction with cerebrovascular compromise. Ann NY Acad Sci 2000; 903:204–221.CrossRefPubMedGoogle Scholar
  9. 9.
    Mosconi L, Pupi A, De Leon MJ. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci 2008; 1147:180–195.CrossRefPubMedGoogle Scholar
  10. 10.
    Farlow MR, Miller ML, Pejovic V. Treatment options in Alzheimer’s disease: maximizing benefit, managing expectations. Dement Geriatr Cogn Disord 2008; 25:408–422.CrossRefPubMedGoogle Scholar
  11. 11.
    Migliore L, Fontana I, Colognato R et al. Searching for the role and the most suitable biomarkers of oxidative stress in Alzheimer’s disease and in other neurodegenerative diseases. Neurobiol Aging 2005; 26:587–595.CrossRefPubMedGoogle Scholar
  12. 12.
    Mancuso M, Orsucci D, Siciliano G et al. Mitochondria, Mitochondrial DNA and Alzheimer’s Disease. What Comes First? Curr Alzh Res 2008; 5:457–468.CrossRefGoogle Scholar
  13. 13.
    Henze K, Martin W. Evolutionary biology: essence of mitochondria. Nature 2003; 426:127–128.CrossRefPubMedGoogle Scholar
  14. 14.
    Chan DC. Mitochondria: Dynamic Organelles in Disease, Aging and Development. Cell 2006; 125:1241–1252.CrossRefPubMedGoogle Scholar
  15. 15.
    Noji H, Yoshida M. The rotary machine of the cell ATP synthase, J Biol Chem 2001; 276:1665–1668.CrossRefPubMedGoogle Scholar
  16. 16.
    DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases N Engl J Med 2003; 348:2656–2668.CrossRefPubMedGoogle Scholar
  17. 17.
    Lackner LL, Nunnari JM. The molecular mechanism and cellular functions of mitochondrial division. Biochim Biophys Acta, In press.Google Scholar
  18. 18.
    Mitchell P, Moyle J. Chemiosmotic hypothesis of oxidative phosphorylation. Nature 1967; 213:137–139.CrossRefPubMedGoogle Scholar
  19. 19.
    Gibson GE, Haroutunian V, Zhang H et al. Mitochondrial damage in Alzheimer’s disease varies with apolipoprotein E genotype. Ann Neurol 2000; 48:297–303.CrossRefPubMedGoogle Scholar
  20. 20.
    Bubber P, Haroutunian V, Fisch G et al. Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol 2005; 57:695–703.CrossRefPubMedGoogle Scholar
  21. 21.
    Liang WS, Reiman EM, Valla J et al. Alzheimer’s disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci USA 2008; 105:4441–4446.CrossRefPubMedGoogle Scholar
  22. 22.
    Valko M, Leibfritz D, Moncol J et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2006; 39:44–84.CrossRefPubMedGoogle Scholar
  23. 23.
    Siciliano G, Piazza S, Carlesi C et al. Antioxidant capacity and protein oxidation in cerebrospinal fluid of amyotrophic lateral sclerosis. J Neurol 2007; 254:575–80.CrossRefPubMedGoogle Scholar
  24. 24.
    Behl C, Davis JB, Lesley R et al. Hydrogen peroxide mediates amyloid b protein toxicity Cell 1994; 77:817–827.CrossRefPubMedGoogle Scholar
  25. 25.
    Sagara Y, Dargusch R, Klier FG et al. Increased antioxidant enzyme activity in amyloid b protein-resistant cells. J Neurosci 1996; 16:497–505.PubMedGoogle Scholar
  26. 26.
    Dyrks T, Dyrks E, Harmann R et al. Amyloidogenicity of bA4 and bA4-bearing amyloid protein precursor fragments by metal-catalyzed oxidation. J Biol Chem 1992; 267:18210–18217.PubMedGoogle Scholar
  27. 27.
    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; 161:41–54.CrossRefPubMedGoogle Scholar
  28. 28.
    Oddo S, Caccamo A, Shepherd JD et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003; 39:409–421.CrossRefPubMedGoogle Scholar
  29. 29.
    Keller JN, Schmitt FA, Scheff SW et al. Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology 2005; 64:1152–1156.PubMedGoogle Scholar
  30. 30.
    Wang J, Markesbery WR, Lovell MA. Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment. J Neurochem 2006; 96: 825–832.CrossRefPubMedGoogle Scholar
  31. 31.
    Migliore L, Fontana I, Trippi F et al. Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiol Aging 2005; 26:567–573.CrossRefPubMedGoogle Scholar
  32. 32.
    Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 1994; 36:747–751.CrossRefPubMedGoogle Scholar
  33. 33.
    Guix FX, Uribesalgo I, Coma M et al. The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol 2005; 76:126–152.CrossRefPubMedGoogle Scholar
  34. 34.
    Wang J, Xiong S, Xie C et al. Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer’s disease. J Neurochem 2005; 93:953–962.CrossRefPubMedGoogle Scholar
  35. 35.
    Butterfield DA. Proteomics: a new approach to investigate oxidative stress in Alzheimer’s disease brain. Brain Res 2004; 1000:1–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Nunomura A, Perry G, Pappolla MA et al. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J Neurosci 1999; 19:1959–1964.PubMedGoogle Scholar
  37. 37.
    Nunomura A, Chiba S, Lippa CF et al. Neuronal RNA oxidation is a prominent feature of familial Alzheimer’s disease. Neurobiol Dis 2004; 17:108–113.CrossRefPubMedGoogle Scholar
  38. 38.
    Honda K, Smith MA, Zhu X et al. Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron. J Biol Chem 2005; 280:20978–20986.CrossRefPubMedGoogle Scholar
  39. 39.
    Aliyev A, Chen SG, Seyidova D et al. Mitochondria DNA deletions in atherosclerotic hypoperfused brain microvessels as a primary target for the development of Alzheimer’s disease. J Neurol Sci 2005; 229–230:285–292.CrossRefPubMedGoogle Scholar
  40. 40.
    Baloyannis SJ. Mitochondrial alterations in Alzheimer’s disease. J Alzheimers Dis 2006; 9:119–126.PubMedGoogle Scholar
  41. 41.
    Trimmer PA, Borland MK. Differentiated Alzheimer’s disease transmitochondrial cybrid cell lines exhibit reduced organelle movement. Antioxid Redox Signal 2005; 7:1101–1109.CrossRefPubMedGoogle Scholar
  42. 42.
    Hauptmann S, Scherping I, Dröse S et al. Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging, in press.Google Scholar
  43. 43.
    Castellani R, Hirai K, Aliev G et al. Role of mitochondrial dysfunction in Alzheimer’s disease. J Neurosci Res 2002; 70:357–360.CrossRefPubMedGoogle Scholar
  44. 44.
    Mutisya EM, Bowling AC, Beal MF. Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem 1994; 63:2179–2184.CrossRefPubMedGoogle Scholar
  45. 45.
    Bosetti F, Brizzi F, Barogi S et al. Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease. Neurobiol Aging 2002; 23:371–376.CrossRefPubMedGoogle Scholar
  46. 46.
    Wong-Riley M, Antuono P, Ho KC et al. Cytochrome oxidase in Alzheimer’s disease: biochemical, histochemical and immunohistochemical analyses of the visual and other systems. Vision Res 1997; 37:3593–3608.CrossRefPubMedGoogle Scholar
  47. 47.
    Valla J, Schneider L, Niedzielko T et al. Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment. Mitochondrion 2006; 6:323–330.CrossRefPubMedGoogle Scholar
  48. 48.
    Mancuso M, Filosto M, Bosetti F et al. Decreased platelet cytochrome c oxidase activity is accompanied by increased blood lactate concentration during exercise in patients with Alzheimer disease. Exp Neurol 2003; 182:421–426.CrossRefPubMedGoogle Scholar
  49. 49.
    Devi L, Prabhu BM, Galati DF et al. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J Neurosci 2006; 26:9057–9068.CrossRefPubMedGoogle Scholar
  50. 50.
    Lustbader JW, Cirilli M, Lin C et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 2004; 304:448–452.CrossRefPubMedGoogle Scholar
  51. 51.
    Hansson CA, Frykman S, Farmery MR et al. Nicastrin, presenilin, APH-1 and PEN-2 form active gamma-secretase complexes in mitochondria. J Biol Chem 2004; 279:51654–51660.CrossRefPubMedGoogle Scholar
  52. 52.
    Leissring MA, Farris W, Wu X et al. Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria. Biochem J 2004; 383:439–446.CrossRefPubMedGoogle Scholar
  53. 53.
    Falkevall A, Alikhani N, Bhushan S et al. Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP. J Biol Chem 2006; 281:29096–29104.CrossRefPubMedGoogle Scholar
  54. 54.
    Atamna H, Frey WH II. A role for heme in Alzheimer’s disease: heme binds amyloid b and has altered metabolism. Proc Natl Acad Sci USA 2004; 101:11153–11158.CrossRefPubMedGoogle Scholar
  55. 55.
    Ohyagi Y, Yamada T, Nishioka K et al. Selective increase in cellular A beta 42 is related to apoptosis but not necrosis. Neuroreport 2000; 11:167–171.CrossRefPubMedGoogle Scholar
  56. 56.
    Drake J, Link CD, Butterfield DA. Oxidative stress precedes fibrillar deposition of Alzheimer’s disease amyloid betapeptide (1–42) in a transgenic Caenorhabditis elegans model. Neurobiol Aging 2003; 24:415–420.CrossRefPubMedGoogle Scholar
  57. 57.
    Fukui H, Diaz F, Garcia S et al. Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2007; 104:14163–14168.CrossRefPubMedGoogle Scholar
  58. 58.
    Fukui H, Moraes CT. The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis? Trends Neurosci, 2008; 31:251–256.CrossRefPubMedGoogle Scholar
  59. 59.
    Cardoso SM, Proenca MT, Santos S et al. Cytochrome c oxidase is decreased in Alzheimer’s disease platelets. Neurobiol Aging 2004; 25:105–110.CrossRefPubMedGoogle Scholar
  60. 60.
    Trimmer PA, Keeney PM, Borland MK et al. Mitochondrial abnormalities in cybrid cell models of sporadic Alzheimer’s disease worsen with passage in culture. Neurobiol Dis 2004; 15:29–39.CrossRefPubMedGoogle Scholar
  61. 61.
    Elson JL, Herrnstadt C, Preston G et al. Does the mitochondrial genome play a role in the etiology of Alzheimer’s disease? Hum Genet 2006; 119:241–254.CrossRefPubMedGoogle Scholar
  62. 62.
    Chagnon P, Gee M, Filion M et al. Phylogenetic analysis of the mitochondrial genome indicates significant differences between patients with Alzheimer disease and controls in a French-Canadian founder population. Am J Med Genet 1999; 85:20–30.CrossRefPubMedGoogle Scholar
  63. 63.
    Carrieri G, Bonafè M, De Luca M et al. Mitochondrial DNA haplogroups and ApoE4 allele are non-independent variables in sporadic Alzheimer’s disease. Hum Genet 2001; 108:194–198.CrossRefPubMedGoogle Scholar
  64. 64.
    van der Walt JM, Dementieva YA, Martin ER et al. Analysis of European mitochondrial haplogroups with Alzheimer disease risk. Neurosci Lett 2004; 365:28–32.CrossRefPubMedGoogle Scholar
  65. 65.
    Chinnery PF, Taylor GA, Howell N et al. Mitochondrial DNA haplogroups and susceptibility to AD and dementia with Lewy bodies. Neurology 2000; 55:302–304.PubMedGoogle Scholar
  66. 66.
    Maruszak A, Canter JA, Styczyńska M et al. Mitochondrial haplogroup H and Alzheimer’s disease-Is there a connection? Neurobiol Aging, In press.Google Scholar
  67. 67.
    Mancuso M, Nardini M, Micheli D et al. Lack of association between mtDNA haplogroups and Alzheimer’s disease in Tuscany. Neurol Sci 2007; 28:142–147.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  • Michelangelo Mancuso
    • 1
  • Daniele Orsucci
    • 1
  • Annalisa LoGerfo
    • 1
  • Valeria Calsolaro
    • 1
  • Gabriele Siciliano
    • 1
  1. 1.Department of Neuroscience Neurological ClinicUniversity of PisaRomaItaly

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