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Journal of Neural Transmission

, Volume 118, Issue 5, pp 747–752 | Cite as

Mechanisms of neurodegeneration shared between multiple sclerosis and Alzheimer’s disease

  • Hans LassmannEmail author
Dementias-Review Article

Abstract

Multiple sclerosis and Alzheimer’s disease are fundamentally different diseases. However, recent data suggest that certain mechanisms of neurodegeneration may be shared between the two diseases. Inflammation drives the disease in multiple sclerosis. It is also present in Alzheimer’s disease lesions, where it may have dual functions in amyloid clearance as well as in the propagation of neurodegeneration. In both diseases, degeneration of neurons, axons, and synapses occur on the background of profound mitochondrial injury. Reactive oxygen and nitric oxide intermediates are major candidates for the induction of mitochondrial injury. Radicals are produced through the induction of the respiratory burst in activated microglia, which are present in the lesions of both diseases. In addition, liberation of toxic iron from intracellular stores may augment radical formation. Finally reactive oxygen species are also produced in the course of mitochondrial injury itself. Anti-oxidant and mitochondria protective therapeutic strategies may be beneficial both in multiple sclerosis and Alzheimer’s disease in particular in early stages of the disease.

Keywords

Multiple sclerosis Alzheimer’s disease Inflammation Mitochondria Oxidative damage 

References

  1. Aboul-Enein F, Rauschka H, Kornek B, Stadelmann C, Stefferl A, Brück W, Lucchinetti CF, Schmidbauer M, Jellinger K, Lassmann H (2003) Preferential loss of myelin associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases. J Neuropath Exp Neurol 62:25–33PubMedGoogle Scholar
  2. Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM (2007) Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci 27:9115–9129PubMedCrossRefGoogle Scholar
  3. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6:916–919PubMedCrossRefGoogle Scholar
  4. Bolanos JP, Almeida A, Stewart V, Peuchen S, Land JM, Clark JB, Heales SJ (1997) Nitric oxide mediated mitochondrial damage in the brain: Mechanisms and implication for neurdegenerative diseases. J Neurochem 68:2227–2240PubMedCrossRefGoogle Scholar
  5. Boutajangout A, Quartermain D, Sigurdsson EM (2010) Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J Neurosci 30:16559–16561PubMedCrossRefGoogle Scholar
  6. Bruce-Keller AJ, Gupta S, Parrino TE, Knight AG, Ebenezar PJ, Weidner AM, LeVine H 3rd, Keller JN, Markesbery WR (2010) NOX activity is increased in mild cognitive impairment. Antioxid Redox Signal 12:1371–1382PubMedCrossRefGoogle Scholar
  7. Brück W, Porada Ph, Poser S, Rieckmann P, Hanefeld F, Kretschmer HA, Lassmann H (1995) Monocyte/macrophage differentiation in early multiple sclerosis. Ann Neurol 38:788–796PubMedCrossRefGoogle Scholar
  8. Butterfield DA, Bader Lange ML, Sultana R (2010) Involvements oft he lipid peroxidation product, HNE, in the pathogenesis and progression of Alzheimer’s disease. Biochem Biophys Acta 1801:924–929PubMedGoogle Scholar
  9. Campbell GR, Ziabreva I, Reeve AK, Krishnan KJ, Reynolds R, Howell O, Lassmann H, Turnbull DM, Mahad DJ (2010) Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol [epub ahead of print]Google Scholar
  10. Castellani R, Hirai K, Aliev G, Drew KL, Nunomura A, Takeda A, Cash AD, Obrenovich ME, Perry G, Smith MA (2002) Role of mitochondrial dysfunction in Alzheimer’s disease. J Neurosci Res 70:357–360PubMedCrossRefGoogle Scholar
  11. Cross AH, Manning PT, Keeling RM, Schmidt RE, Misko TP (1998) Peroxynitrite formation within the central nervous system in active multiple sclerosis. J Neuroimmunol 88:45–56PubMedCrossRefGoogle Scholar
  12. Dal Bianco A, Bradl M, Frischer J, Kutzelnigg A, Jellinger K, Lassmann H (2008) Multiple sclerosis and Alzheimer’s disease. Ann Neurol 63(2):174–183PubMedCrossRefGoogle Scholar
  13. De la Monte SM, Wands JR (2006) Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer’s disease. J Alzheimers Dis 9:167–181Google Scholar
  14. Devi L, Anandatheerthavaranda HK (2010) Mitochondrial trafficking of APP and alpha synuclein: Relevance to mitochondrial dysfunction in Alzheimer’s and Parkinson’s diseases. Biochem Biophys Acta 1801:11–19Google Scholar
  15. Di Filippo M, Chasserini D, Tozzi A, Picconi B, Calabresi P (2010) Mitochondria and the link between neuroinflammation and neurodegeneration. J Alzheimer’s Disease 20:S369–S379Google Scholar
  16. Diaz-Sanchez M, Williams K, DeLuca GC, Esiri MM (2006) Protein co-expression with axonal injury in multiple sclerosis plaques. Acta Neuropathol 111:289–299PubMedCrossRefGoogle Scholar
  17. Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, Rudick R, Mirnics K, Trapp BD (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59:478–489PubMedCrossRefGoogle Scholar
  18. Eckert A, Schulz KL, Rhein V, Götz J (2010) Convergence of amyloid-beta and tau pathologies on mitochondria in vivo. Mol Neurobiol 41:107–114PubMedCrossRefGoogle Scholar
  19. Frenkel D, Maron R, Burt DS, Weiner HL (2005) Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease. J Clin Invest 115:2423–2433PubMedCrossRefGoogle Scholar
  20. Frischer JM, Bramow S, Dal Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H (2009) The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132:1175–1189PubMedCrossRefGoogle Scholar
  21. Gandhi KS, McKay FC, Cox M, Riveros C, Armstrong N, Head RN, Vucic S, Williams DW, Stankovich J, Brown M, Danoy P, Stewart GJ, Broadley S, Moscato P, Lechner-Scott J, Scott RJ, Both DR, ANZgene Multiple Sclerosis Genetics Consortium (2010) The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis. Hum Mol Genet 19:2134–2143PubMedCrossRefGoogle Scholar
  22. Giacomini PS, Darlington PJ, Bar-Or A (2009) Emerging multiple sclerosis disease-modifying therapies. Curr Opin Neurol 22:226–232PubMedCrossRefGoogle Scholar
  23. Hallgren B, Sournader P (1958) The effect of age on the non-haemin iron in the human brain. J Neurochem 3:41–51PubMedCrossRefGoogle Scholar
  24. Hallgren B, Sournader P (1960) The non haemin iron in the cerebral cortex in Alzheimer’s disease. J Neurochem 5:307–310PubMedCrossRefGoogle Scholar
  25. Higgins GC, Beart PM, Shin YS, Chen MJ, Cheung NS, Nagley P (2010) Oxidative stress: emerging mitochondrial and cellular themes and variations in neuronal injury. J Alzheimer’s disease 20:S453–S473Google Scholar
  26. Hirai K, Aliev G, Nunomura A, Fujioka H, Russel RL, Attwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023PubMedGoogle Scholar
  27. Hochmeister S, Grundtner R, Bauer J, Engelhardt B, Lyck R, Gordon G, Korosec T, Kutzelnigg A, Berger JJ, Bradl M, Bittner RE, Lassmann H (2006) Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis. J Neuropathol Exp Neurol 65:855–865PubMedCrossRefGoogle Scholar
  28. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Totova E, Nicoll JA (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controoed phase I trial. Lancet 372:216–223PubMedCrossRefGoogle Scholar
  29. Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH (2009) Systemic inflammation and disease progression in Alzheimer disease. Neurology 73:768–774PubMedCrossRefGoogle Scholar
  30. Holtzman DM (2008) Moving towards a vaccine. Nature 454:418–420PubMedCrossRefGoogle Scholar
  31. International Multiple Sclerosis Genetics Consortium (IMSGC) (2010) Evidence for polygenic susceptibility to multiple sclerosis—the shape of things to come. Amer J Hum Genet 86:621–625CrossRefGoogle Scholar
  32. Jellinger K (2006) Alzheimer 100–highlights in the history of Alzheimer research. J Neural Transm 113:1603–1623PubMedCrossRefGoogle Scholar
  33. Jellinger K, Paulus W, Grundke-Iqbal I, Riederer P, Youdim MB (1990) Brain iron and ferritin in Parkinson’s and Alzheimer’s diseases. J Neural Trasnm 2:327–340CrossRefGoogle Scholar
  34. Lassmann H, Brück W, Lucchinetti C (2007) The immunopathology of multiple sclerosis: an overview. Brain Pathol 17:210–218PubMedCrossRefGoogle Scholar
  35. Liu JSH, Zhao ML, Brosnan CF, Lee SC (2001) Expression of indicible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Amer J Pathol 158:2057–2066CrossRefGoogle Scholar
  36. Mahad D, Ziabreva I, Lassmann H, Turnbull D (2008) Mitochondrial defects in acute multiple sclerosis lesions. Brain 131:1722–1735PubMedCrossRefGoogle Scholar
  37. Mahad D, Ziabreva I, Campbell G, Lax N, Hanson PS, Lassmann H, Turnbull DH (2009) Mitochondrial changes within axons in multiple sclerosis. Brain 132:1161–1174PubMedCrossRefGoogle Scholar
  38. Markesbery WR, Lovell MA (1998) Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease. Neurobiol Aging 19:33–36PubMedCrossRefGoogle Scholar
  39. McGeer PL, McGeer EG (2007) NSAIDs and Alzheimer disease: epidemiologicaö, animal model and clinical studies. Neurobiol Aging 28:639–647PubMedCrossRefGoogle Scholar
  40. McGeer PL, Rogers J, McGeer EG (2006) Inflammation, anti-inflammatory agents and Alzheimer’s disease: the last 12 years. J Alzheimers Dis 9(3 Suppl):271–276PubMedGoogle Scholar
  41. Mecocci P, MacGarvey U, Beal MF (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 36:747–751PubMedCrossRefGoogle Scholar
  42. Montine KS, Olson SJ, Amarnath V, Whetsell WO, Graham DG, Mintine TJ (1997) Immunohistochemical detection of 4-hydroxy-2-nonenal adducts in Alzheimer’s disease is associated with inheritance of APOE4. Amer J Pathol 150:437–443Google Scholar
  43. Montine KS, Reich E, Neely MD, Sidell KR, Olson SJ, Markesbery WR, Montine TJ (1998) Distribution of reducible 4-hydroxynonenal adduct immunoreactivity in Alzheimer disease is associated with APOE genotype. J Neuropath Exp Neurol 57:415–425PubMedCrossRefGoogle Scholar
  44. Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G (2010) Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochem Biophys Acta 1802:2–10PubMedGoogle Scholar
  45. Nicoll JA, Wilkinson D, Holmes C, Steart P, Marham H, Weller RO (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9:448–452PubMedCrossRefGoogle Scholar
  46. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropath Exp Neurol 60:759–767PubMedGoogle Scholar
  47. Nunomura A, Chiba S, Lippa CF, Cras P, Kalaria RN, Takeda A, Honda K, Smith MA, Perry G (2004) Neuronal RNA oxidation is a prominent feature of familial Alzheimer’s disease. Neurobiol Dis 17:108–113PubMedCrossRefGoogle Scholar
  48. Nunomura A, Hofer T, Moreira PI, Castellani RJ, Smith MA, Perry G (2009) RNA oxidation in Alzheimer disease and related neurodegenerative disorders. Acta Neuropathol 118:151–166PubMedCrossRefGoogle Scholar
  49. Perry G, Sayre LM, Atwood CS, Castellani RJ, Cash AD, Rottkamp CA, Smith MA (2002) The role of iron and copper in the aetiology of neurodegenerative disorders: therapeutic implications. CNS Drugs 16:339–352PubMedCrossRefGoogle Scholar
  50. Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6:193–201PubMedCrossRefGoogle Scholar
  51. Reed TT, Pierce WM, Markesbery WR, Butterfield DA (2009) Proteomic identification of HNE-bound proteins in early Alzheimer disease: Insights into the role of lipid peroxidation in the progression of AD. Brain Res 1274:66–76PubMedCrossRefGoogle Scholar
  52. Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, Meier F, Ozmen L, Bluethmann H, Dröse U, Savaskan E, Czech C, Götz J, Eckert A (2009) Amyloid.beta and tau synergistically impair the oxidative phosphorylation system in tripple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci USA 106:20057–20062PubMedGoogle Scholar
  53. Rosenmann H, Grigoriadis N, Karussis D, Boimel M, Touloumi O, Ovaida H, Abramsky O (2006) Taupopathy-like abnormalities and neurological deficits in mice immunized with neuronal tau protein. Arch Neurol 63:1459–1467PubMedCrossRefGoogle Scholar
  54. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenl′ko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177PubMedCrossRefGoogle Scholar
  55. Sharma R, Fischer MT, Bauer J, Felts PA, Smith KJ, Misu T, Fujihara K, Bradl M, Lassmann H (2010) Inflammation induced by innate immunity in the central nervous system leads to primary astrocyte dysfunction followed by demyelination. Acta Neuropathol 120(2):223–236PubMedCrossRefGoogle Scholar
  56. Shimohama S, Tanino H, Kawakami N, Okamura N, Kodama Y, Yamaguchi T, Hayakawa T, Nunomura A, Chiba S, Perry G, Smith MA, Fujimoto S (2000) Activation of NADPH oxidase in Alzheimer’s disease brains. Biochem Biophys Res Commun 273:5–9PubMedCrossRefGoogle Scholar
  57. Te Koppele JM, Lucassen PJ, Sakkee AN, Van Asten JG, Ravid R, Swaab DF, Van Bezooijen CF (1996) 8OHdG levels in brain do not indicate oxidative DNA damage in Alzheimer’s disease. Neurobiol Aging 17:819–826PubMedCrossRefGoogle Scholar
  58. Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, Oda T, Tsuchiya K, Kosaka K (2002) Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J Neuroimmunol 124:83–92PubMedCrossRefGoogle Scholar
  59. Trapp BD, Nave KA (2008) Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 31:247–269PubMedCrossRefGoogle Scholar
  60. Trapp B, Stys P (2009) Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurology 8:80–291CrossRefGoogle Scholar
  61. Van Horssen J, Schreibelt G, Drexhage J, Hazes T, Dijkstra CD, van der Valk P, de Vires HE (2008) Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radical Biol Med 45:1729–1737CrossRefGoogle Scholar
  62. Van Horssen J, Witte ME, Schreibelt G, de Vries HE (2011) Radical changes in multiple sclerosis pathogenesis. Biochem Biophys Acta 1812:141–150PubMedGoogle Scholar
  63. Veto S, Acs P, Bauer J, Lassmann H, Berente Z, Setalo G Jr, Borgulya G, Sumegi B, Komoly S, Gallyas F Jr, Illes Z (2010) Inhibiting poly(ADP-ribose) polymerase: a potential therapy against oligodendrocyte death. Brain 133:822–834PubMedCrossRefGoogle Scholar
  64. Wiendl H, Hohlfeld R (2009) Multiple sclerosis therapeutics: unexpected outcomes clouding undisputed successes. Neurology 72:1008–1015PubMedCrossRefGoogle Scholar
  65. Wilkinson BL, Landreth GE (2006) The microglial NADPH oxidase complex of oxidative stress in Alzheimer’s disease. J Neuroinflammation 3:30PubMedCrossRefGoogle Scholar
  66. Witte ME, Geurts JJ, de Vires HE, van der Valk P, van Horssen J (2010) Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration. Mitochondrion 10:411–418PubMedCrossRefGoogle Scholar
  67. Ziabreva I, Campbell G, Rist J, Zambonin J, Rorbach J, Wydro MM, Lassmann H, Franklin RJ, Mahad D (2010) Injury and differentiation following inhibition of mitochondrial respiratory chain complex IV in rat oligodendrocytes. Glia 58:1827–1837PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Center for Brain ResearchMedical University of ViennaWienAustria

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