Molecular Neurobiology

, Volume 46, Issue 1, pp 194–204

Peripheral Mitochondrial Dysfunction in Alzheimer’s Disease: Focus on Lymphocytes

  • Kristina Leuner
  • Kathrin Schulz
  • Tanja Schütt
  • Johannes Pantel
  • David Prvulovic
  • Virginie Rhein
  • Egemen Savaskan
  • Christian Czech
  • Anne Eckert
  • Walter E. Müller
Article

Abstract

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will increase with increased life expectancy. The AD brain is marked by severe neurodegeneration like the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems in the hippocampus and cerebral cortex. Recent findings suggest that these pathological changes are causally induced by mitochondrial dysfunction and increased oxidative stress. These changes are not only observed in the brain of AD patients but also in the periphery. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and especially mitochondrial dysfunction as peripheral markers for the detection of AD in blood cells especially in lymphocytes. We discuss recent not otherwise published findings on the level of complex activities of the respiratory chain comprising mitochondrial respiration and the mitochondrial membrane potential (MMP). We obtained decreased basal MMP levels in lymphocytes from AD patients as well as enhanced sensitivity to different complex inhibitors of the respiratory chain. These changes are in line with mitochondrial defects obtained in AD cell and animal models, and in post-mortem AD tissue. Importantly, these mitochondrial alterations where not only found in AD patients but also in patients with mild cognitive impairment (MCI). These new findings point to a relevance of mitochondrial function as an early peripheral marker for the detection of AD and MCI.

Keywords

Alzheimer’s disease Mild cognitive impairment Mitochondrial membrane potential Reactive oxygen species Peripheral tissues Lymphocytes 

References

  1. 1.
    Mattson MP, Magnus T (2006) Ageing and neuronal vulnerability. Nat Rev Neurosci 4:278–294CrossRefGoogle Scholar
  2. 2.
    Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 4:483–495CrossRefGoogle Scholar
  3. 3.
    Sastre J, Pallardo FV, de la Asuncion JG, Vina J (2000) Mitochondria, oxidative stress and aging. Free Radic Res 3:189–198CrossRefGoogle Scholar
  4. 4.
    Floyd RA, Hensley K (2002) Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol Aging 5:795–807CrossRefGoogle Scholar
  5. 5.
    Onyango IG, Lu JH, Rodova M, Lezi E, Crafter AB, Swerdlow RH (2010) Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim Biophys Acta 1:228–234Google Scholar
  6. 6.
    Marchi S, Giorgi C, Suski JM, Agnoletto C, Bononi A, Bonora M, De Marchi E, Missiroli S, Patergnani S, Poletti F et al (2012) Mitochondria-ros crosstalk in the control of cell death and aging. J Signal Transduct (in press)Google Scholar
  7. 7.
    Atamna H (2004) Heme, iron, and the mitochondrial decay of ageing. Ageing Res Rev 3:303–318PubMedCrossRefGoogle Scholar
  8. 8.
    Mattson MP (2006) Neuronal life-and-death signaling, apoptosis, and neurodegenerative disorders. Antioxid Redox Signal 11–12:1997–2006CrossRefGoogle Scholar
  9. 9.
    Leuner K, Schutt T, Kurz C, Eckert SH, Schiller C, Occhipinti A, Mai S, Jendrach M, Eckert GP, Kruse SE et al (2012) Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation. Antioxid Redox Signal 16(12):1421–1433PubMedCrossRefGoogle Scholar
  10. 10.
    Hauptmann S, Scherping I, Drose S, Brandt U, Schulz KL, Jendrach M, Leuner K, Eckert A, Muller WE (2009) Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging 10:1574–1586CrossRefGoogle Scholar
  11. 11.
    Bonda DJ, Wang X, Perry G, Nunomura A, Tabaton M, Zhu X, Smith MA (2010) Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology 4–5:290–294CrossRefGoogle Scholar
  12. 12.
    Reddy PH (2009) Role of mitochondria in neurodegenerative diseases: mitochondria as a therapeutic target in Alzheimer's disease. CNS Spectr 8(Suppl 7):8–13Google Scholar
  13. 13.
    Munch G, Schinzel R, Loske C, Wong A, Durany N, Li JJ, Vlassara H, Smith MA, Perry G, Riederer P (1998) Alzheimer’s disease–synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts. J Neural Transm 4–5:439–461CrossRefGoogle Scholar
  14. 14.
    Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 2:101–112CrossRefGoogle Scholar
  15. 15.
    Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 4:329–344CrossRefGoogle Scholar
  16. 16.
    Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, Meier F, Ozmen L, Bluethmann H, Drose S, Brandt U et al (2009) Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice. Proc Natl Acad Sci U S A 47:20057–20062Google Scholar
  17. 17.
    David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, Rizzu P, Ravid R, Drose S, Brandt U, Muller WE et al (2005) Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L Tau transgenic mice. J Biol Chem 25:23802–23814CrossRefGoogle Scholar
  18. 18.
    Gibson GE, Huang HM (2005) Oxidative stress in Alzheimer’s disease. Neurobiol Aging 5:575–578CrossRefGoogle Scholar
  19. 19.
    Ankarcrona M, Winblad B (2005) Biomarkers for apoptosis in Alzheimer’s disease. Int J Geriatr Psychiatry 2:101–105CrossRefGoogle Scholar
  20. 20.
    Leuner K, Pantel J, Frey C, Schindowski K, Schulz K, Wegat T, Maurer K, Eckert A, Muller WE (2007) Enhanced apoptosis, oxidative stress and mitochondrial dysfunction in lymphocytes as potential biomarkers for Alzheimer’s disease. J Neural Transm Suppl 72:207–215PubMedCrossRefGoogle Scholar
  21. 21.
    Sultana R, Mecocci P, Mangialasche F, Cecchetti R, Baglioni M, Butterfield DA (2011) Increased protein and lipid oxidative damage in mitochondria isolated from lymphocytes from patients with Alzheimer’s disease: insights into the role of oxidative stress in Alzheimer's disease and initial investigations into a potential biomarker for this dementing disorder. J Alzheimers Dis 1:77–84Google Scholar
  22. 22.
    Cecchi C, Fiorillo C, Nassi P, Liguri G, Sorbi S, Latorraca S, Bagnoli S (2002) Oxidative injury and antioxidant defences in peripheral cells from Alzheimer patients. Neurobiol Aging (Suppl 1):S513–S513Google Scholar
  23. 23.
    Moreira PI, Harris PL, Zhu X, Santos MS, Oliveira CR, Smith MA, Perry G (2007) Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts. J Alzheimers Dis 2:195–206Google Scholar
  24. 24.
    Naderi J, Lopez C, Pandey S (2006) Chronically increased oxidative stress in fibroblasts from Alzheimer’s disease patients causes early senescence and renders resistance to apoptosis by oxidative stress. Mech Ageing Dev 1:25–35CrossRefGoogle Scholar
  25. 25.
    Kawamoto EM, Munhoz CD, Glezer I, Bahia VS, Caramelli P, Nitrini R, Gorjao R, Curi R, Scavone C, Marcourakis T (2005) Oxidative state in platelets and erythrocytes in aging and Alzheimer’s disease. Neurobiol Aging 6:857–864CrossRefGoogle Scholar
  26. 26.
    Valla J, Schneider L, Niedzielko T, Coon KD, Caselli R, Sabbagh MN, Ahern GL, Baxter L, Alexander G, Walker DG et al (2006) Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment. Mitochondrion 6:323–330PubMedCrossRefGoogle Scholar
  27. 27.
    Shi C, Guo K, Yew DT, Yao Z, Forster EL, Wang H, Xu J (2008) Effects of ageing and Alzheimer’s disease on mitochondrial function of human platelets. Exp Gerontol 6:589–594CrossRefGoogle Scholar
  28. 28.
    Casoli T, Di Stefano G, Giorgetti B, Balietti M, Recchioni R, Moroni F, Marcheselli F, Bernardini G, Fattoretti P, Bertoni-Freddari C (2008) Platelet as a physiological model to investigate apoptotic mechanisms in Alzheimer beta-amyloid peptide production. Mech Ageing Dev 3:154–162CrossRefGoogle Scholar
  29. 29.
    Cristalli DO, Arnal N, Marra FA, de Alaniz MJ, Marra CA (2012) Peripheral markers in neurodegenerative patients and their first-degree relatives. J Neurol Sci 1–2:48–56CrossRefGoogle Scholar
  30. 30.
    Torres LL, Quaglio NB, de Souza GT, Garcia RT, Dati LM, Moreira WL, Loureiro AP, Souza-Talarico JN, Smid J, Porto CS et al (2011) Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 1:59–68Google Scholar
  31. 31.
    Baldeiras I, Santana I, Proenca MT, Garrucho MH, Pascoal R, Rodrigues A, Duro D, Oliveira CR (2008) Peripheral oxidative damage in mild cognitive impairment and mild Alzheimer’s disease. J Alzheimers Dis 1:117–128Google Scholar
  32. 32.
    Schindowski K, Eckert A, Peters J, Gorriz C, Schramm U, Weinandi T, Maurer K, Frolich L, Muller WE (2007) Increased T-cell reactivity and elevated levels of CD8+ memory T-cells in Alzheimer's disease-patients and T-cell hyporeactivity in an Alzheimer’s disease-mouse model: implications for immunotherapy. Neuromol Med 4:340–354CrossRefGoogle Scholar
  33. 33.
    Huang HM, Fowler C, Xu H, Zhang H, Gibson GE (2005) Mitochondrial function in fibroblasts with aging in culture and/or Alzheimer’s disease. Neurobiol Aging 6:839–848CrossRefGoogle Scholar
  34. 34.
    Schindowski K, Kratzsch T, Peters J, Steiner B, Leutner S, Touchet N, Maurer K, Czech C, Pradier L, Frolich L et al (2003) Impact of aging: sporadic, and genetic risk factors on vulnerability to apoptosis in Alzheimer’s disease. Neuromol Med 3:161–178CrossRefGoogle Scholar
  35. 35.
    Drouet M, Lauthier F, Charmes JP, Sauvage P, Ratinaud MH (1999) Age-associated changes in mitochondrial parameters on peripheral human lymphocytes. Exp Gerontol 7:843–852CrossRefGoogle Scholar
  36. 36.
    Kadioglu E, Sardas S, Aslan S, Isik E, Esat KA (2004) Detection of oxidative DNA damage in lymphocytes of patients with Alzheimer’s disease. Biomarkers 2:203–209CrossRefGoogle Scholar
  37. 37.
    Leutner S, Schindowski K, Frolich L, Maurer K, Kratzsch T, Eckert A, Muller WE (2005) Enhanced ROS-generation in lymphocytes from Alzheimer’s patients. Pharmacopsychiatry 6:312–315CrossRefGoogle Scholar
  38. 38.
    De Leo ME, Borrello S, Passantino M, Palazzotti B, Mordente A, Daniele A, Filippini V, Galeotti T, Masullo C (1998) Oxidative stress and overexpression of manganese superoxide dismutase in patients with Alzheimer’s disease. Neurosci Lett 3:173–176CrossRefGoogle Scholar
  39. 39.
    Morocz M, Kalman J, Juhasz A, Sinko I, McGlynn AP, Downes CS, Janka Z, Rasko I (2002) Elevated levels of oxidative DNA damage in lymphocytes from patients with Alzheimer’s disease. Neurobiol Aging 1:47–53CrossRefGoogle Scholar
  40. 40.
    Cecchi C, Fiorillo C, Sorbi S, Latorraca S, Nacmias B, Bagnoli S, Nassi P, Liguri G (2002) Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer’s patients. Free Radic Biol Med 10:1372–1379CrossRefGoogle Scholar
  41. 41.
    Mecocci P, Cherubini A, Senin U (1997) Increased oxidative damage in lymphocytes of Alzheimer’s disease patients. J Am Geriatr Soc 12:1536–1537Google Scholar
  42. 42.
    Mecocci P, Polidori MC, Cherubini A, Ingegni T, Mattioli P, Catani M, Rinaldi P, Cecchetti R, Stahl W, Senin U et al (2002) Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease. Arch Neurol 5:794–798CrossRefGoogle Scholar
  43. 43.
    Migliore L, Fontana I, Trippi F, Colognato R, Coppede F, Tognoni G, Nucciarone B, Siciliano G (2005) Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiol Aging 5:567–573CrossRefGoogle Scholar
  44. 44.
    Straface E, Matarrese P, Gambardella L, Vona R, Sgadari A, Silveri MC, Malorni W (2005) Oxidative imbalance and cathepsin D changes as peripheral blood biomarkers of Alzheimer disease: a pilot study. FEBS Lett 13:2759–2766CrossRefGoogle Scholar
  45. 45.
    Dezor M, Dorszewska J, Florczak J, Kempisty B, Jaroszewska-Kolecka J, Rozycka A, Polrolniczak A, Bugaj R, Jagodzinski PP, Kozubski W (2011) Expression of 8-oxoguanine DNA glycosylase 1 (OGG1) and the level of p53 and TNF-alpha proteins in peripheral lymphocytes of patients with Alzheimer’s disease. Folia Neuropathol 2:123–131Google Scholar
  46. 46.
    Cecchi C, Latorraca S, Sorbi S, Iantomasi T, Favilli F, Vincenzini MT, Liguri G (1999) Gluthatione level is altered in lymphoblasts from patients with familial Alzheimer’s disease. Neurosci Lett 2:152–154CrossRefGoogle Scholar
  47. 47.
    Schuessel K, Frey C, Jourdan C, Keil U, Weber CC, Muller-Spahn F, Muller WE, Eckert A (2006) Aging sensitizes toward ROS formation and lipid peroxidation in PS1M146L transgenic mice. Free Radic Biol Med 5:850–862CrossRefGoogle Scholar
  48. 48.
    Eckert A, Schindowski K, Leutner S, Luckhaus C, Touchet N, Czech C, Muller WE (2001) Alzheimer’s disease-like alterations in peripheral cells from presenilin-1 transgenic mice. Neurobiol Dis 2:331–342CrossRefGoogle Scholar
  49. 49.
    Schindowski K, Leutner S, Muller WE, Eckert A (2000) Age-related changes of apoptotic cell death in human lymphocytes. Neurobiol Aging 5:661–670CrossRefGoogle Scholar
  50. 50.
    Schindowski K, Peters J, Gorriz C, Schramm U, Weinandi T, Leutner S, Maurer K, Frolich L, Muller WE, Eckert A (2006) Apoptosis of CD4+ T and natural killer cells in Alzheimer’s disease. Pharmacopsychiatry 6:220–228CrossRefGoogle Scholar
  51. 51.
    Eckert A, Keil U, Marques CA, Bonert A, Frey C, Schussel K, Muller WE (2003) Mitochondrial dysfunction, apoptotic cell death, and Alzheimer’s disease. Biochem Pharmacol 8:1627–1634CrossRefGoogle Scholar
  52. 52.
    Eckert A, Oster M, Zerfass R, Hennerici M, Muller WE (2001) Elevated levels of fragmented DNA nucleosomes in native and activated lymphocytes indicate an enhanced sensitivity to apoptosis in sporadic Alzheimer’s disease—specific differences to vascular dementia. Demen Geriatr Cogn Disord 2:98–105CrossRefGoogle Scholar
  53. 53.
    Eckert A, Steiner B, Marques C, Leutz S, Romig H, Haass C, Muller WE (2001) Elevated vulnerability to oxidative stress-induced cell death and activation of caspase-3 by the Swedish amyloid precursor protein mutation. J Neurosci Res 2:183–192CrossRefGoogle Scholar
  54. 54.
    Gatta L, Cardinale A, Wannenes F, Consoli C, Armani A, Molinari F, Mammi C, Stocchi F, Torti M, Rosano GM et al (2009) Peripheral blood mononuclear cells from mild cognitive impairment patients show deregulation of Bax and Sod1 mRNAs. Neurosci Lett 1:36–40CrossRefGoogle Scholar
  55. 55.
    Frey C, Bonert A, Kratzsch T, Rexroth G, Rosch W, Muller-Spahn F, Maurer K, Muller WE, Eckert A (2006) Apolipoprotein E epsilon 4 is associated with an increased vulnerability to cell death in Alzheimer’s disease. J Neural Transm 11:1753–1761CrossRefGoogle Scholar
  56. 56.
    Tacconi S, Perri R, Balestrieri E, Grelli S, Bernardini S, Annichiarico R, Mastino A, Caltagirone C, Macchi B (2004) Increased caspase activation in peripheral blood mononuclear cells of patients with Alzheimer’s disease. Exp Neurol 1:254–262CrossRefGoogle Scholar
  57. 57.
    Lombardi VR, Fernandez-Novoa L, Etcheverria I, Seoane S, Cacabelos R (2004) Association between APOE epsilon4 allele and increased expression of CD95 on T cells from patients with Alzheimer’s disease. Methods Find Exp Clin Pharmacol 7:523–529CrossRefGoogle Scholar
  58. 58.
    Schindowski K, Frohlich L, Maurer K, Muller WE, Eckert A (2002) Age-related impairment of human T lymphocytes’ activation: specific differences between CD4(+) and CD8(+) subsets. Mech Ageing Develop 4:375–390CrossRefGoogle Scholar
  59. 59.
    Huang YD (2006) Apolipoprotein E and Alzheimer disease. Neurology 66:S79–S85PubMedCrossRefGoogle Scholar
  60. 60.
    Parshad R, Sanford KK, Price FM, Melnick LK, Nee LE, Schapiro MB, Tarone RE, Robbins JH (1996) Fluorescent light-induced chromatid breaks distinguish Alzheimer disease cells from normal cells in tissue culture. Proc Natl Acad Sci U S A 10:5146–5150CrossRefGoogle Scholar
  61. 61.
    Cardoso SM, Proenca MT, Santos S, Santana I, Oliveira CR (2004) Cytochrome c oxidase is decreased in Alzheimer’s disease platelets. Neurobiol Aging 1:105–110CrossRefGoogle Scholar
  62. 62.
    Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA, Murri L, Rapoport SI, Solaini G (2002) Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease. Neurobiol Aging 3:371–376CrossRefGoogle Scholar
  63. 63.
    Mancuso M, Filosto M, Bosetti F, Ceravolo R, Rocchi A, Tognoni G, Manca ML, Solaini G, Siciliano G, Murri L (2003) Decreased platelet cytochrome c oxidase activity is accompanied by increased blood lactate concentration during exercise in patients with Alzheimer disease. Exp Neurol 2:421–426CrossRefGoogle Scholar
  64. 64.
    Molina JA, deBustos F, JimenezJimenez FJ, BenitoLeon J, Gasalla T, OrtiPareja M, Vela L, Bermejo F, Martin MA, Campos Y et al (1997) Respiratory chain enzyme activities in isolated mitochondria of lymphocytes from patients with Alzheimer’s disease. Neurology 3:636–638CrossRefGoogle Scholar
  65. 65.
    Casademont J, Miro O, Rodriguez-Santiago B, Viedma P, Blesa R, Cardellach F (2003) Cholinesterase inhibitor rivastigmine enhance the mitochondrial electron transport chain in lymphocytes of patients with Alzheimer’s disease. J Neurol Sci 1:23–26CrossRefGoogle Scholar
  66. 66.
    Culmsee C, Landshamer S (2006) Molecular insights into mechanisms of the cell death program: role in the progression of neurodegenerative disorders. Curr Alzheimer Res 4:269–283CrossRefGoogle Scholar
  67. 67.
    Schuessel K, Leutner S, Cairns NJ, Muller WE, Eckert A (2004) Impact of gender on upregulation of antioxidant defence mechanisms in Alzheimer’s disease brain. J Neural Transm 9:1167–1182Google Scholar
  68. 68.
    Keil U, Bonert A, Marques CA, Scherping I, Weyermann J, Strosznajder JB, Muller-Spahn F, Haass C, Czech C, Pradier L et al (2004) Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem 48:50310–50320CrossRefGoogle Scholar
  69. 69.
    Rhein V, Baysang G, Rao S, Meier F, Bonert A, Muller-Spahn F, Eckert A (2009) Amyloid-beta leads to impaired cellular respiration, energy production and mitochondrial electron chain complex activities in human neuroblastoma cells. Cell Mol Neurobiol 6–7:1063–1071CrossRefGoogle Scholar
  70. 70.
    Petersen RC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med 3:183–194CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Kristina Leuner
    • 6
  • Kathrin Schulz
    • 1
  • Tanja Schütt
    • 1
  • Johannes Pantel
    • 2
  • David Prvulovic
    • 3
  • Virginie Rhein
    • 4
  • Egemen Savaskan
    • 5
  • Christian Czech
    • 7
  • Anne Eckert
    • 4
  • Walter E. Müller
    • 1
    • 8
  1. 1.Department of Pharmacology, BiocenterGoethe UniversityFrankfurtGermany
  2. 2.Institute of General PracticeGoethe UniversityFrankfurtGermany
  3. 3.Department of Psychiatry, Psychosomatic Medicine and PsychotherapyGoethe UniversityFrankfurtGermany
  4. 4.Neurobiology LaboratoryPsychiatric University ClinicsBaselSwitzerland
  5. 5.Gerontopsychiatry, Psychiatric University ClinicsBaselSwitzerland
  6. 6.Clinical and Molecular PharmacyErlangen UniversityErlangenGermany
  7. 7.Hoffmann-La-Roche AG, Pharma Research, NeurosciencesBaselSwitzerland
  8. 8.Pharmakologisches Institut für NaturwissenschaftlerFrankfurtGermany

Personalised recommendations