Molecular Neurobiology

, Volume 46, Issue 1, pp 186–193 | Cite as

From Mitochondrial Dysfunction to Amyloid Beta Formation: Novel Insights into the Pathogenesis of Alzheimer’s Disease

  • Kristina LeunerEmail author
  • Walter E. Müller
  • Andreas S. Reichert


The non-Mendelian sporadic Alzheimer’s disease (AD) is the most frequent form of dementia diagnosed worldwide. The most important risk factor to develop sporadic AD is aging itself. Next to hyperphosphorylated Tau, intracellular amyloid beta (Aß) oligomers are known to initiate a cascade of pathological events ranging from mitochondrial dysfunction, synaptic dysfunction, oxidative stress, and loss of calcium regulation, to inflammation. All these events are considered to play an important role in the progressive loss of neurons. The molecular mechanisms determining the balance between Aß production and clearance during the progression of the disease are not well understood. Furthermore, there is cumulating evidence that Aß formation impairs mitochondrial function and that mitochondrial dysfunction is an early event in the pathogenesis of AD. On the other hand, mitochondrial dysfunction, in particular increased formation of mitochondrially derived reactive oxygen species, promote Aß formation. Here, we review these latest findings linking mitochondrial dysfunction and Aß formation. We propose that mitochondrial dysfunction, which is well-known to increase with age, is an initial trigger for Aß production. As Aß itself further accelerates mitochondrial dysfunction and oxidative stress, its formation is self-stimulated. Taken together, a vicious cycle is initiated that originates from mitochondrial dysfunction, implying that AD can be viewed as an age-associated mitochondrial disorder. The proposed mechanism sheds new light on the pathophysiological changes taking place during the progression of AD as well as in the aging process.


Alzheimer’s disease Amyloid beta formation Aging Mitochondrial dysfunction 


  1. 1.
    Qiu C, Kivipelto M, von Strauss E (2009) Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci 2:111–128Google Scholar
  2. 2.
    Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 4:329–344CrossRefGoogle Scholar
  3. 3.
    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
  4. 4.
    Leuner K, Hauptmann S, Abdel-Kader R, Scherping I, Keil U, Strosznajder JB, Eckert A, Muller WE (2007) Mitochondrial dysfunction: the first domino in brain aging and Alzheimer’s disease? Antioxid Redox Signal 10:1659–1675CrossRefGoogle Scholar
  5. 5.
    Mao P, Reddy PH (2011) Aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer’s disease: implications for early intervention and therapeutics. Biochim Biophys Acta 11:1359–1370Google Scholar
  6. 6.
    Starkov AA (2008) The role of mitochondria in reactive oxygen species metabolism and signaling. Ann NY Acad Sci 37–52Google Scholar
  7. 7.
    Drose S, Brandt U (2008) The mechanism of mitochondrial superoxide production by the cytochrome bc1 complex. J Biol Chem 31:21649–21654CrossRefGoogle Scholar
  8. 8.
    Mattson MP, Magnus T (2006) Ageing and neuronal vulnerability. Nat Rev Neurosci 4:278–294CrossRefGoogle Scholar
  9. 9.
    Scherz-Shouval R, Elazar Z (2011) Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 1:30–38CrossRefGoogle Scholar
  10. 10.
    Clark TA, Lee HP, Rolston RK, Zhu X, Marlatt MW, Castellani RJ, Nunomura A, Casadesus G, Smith MA, Lee HG et al (2010) Oxidative stress and its implications for future treatments and management of Alzheimer disease. Int J Biomed Sci 3:225–227Google Scholar
  11. 11.
    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
  12. 12.
    Leutner S, Eckert A, Muller WE (2001) ROS generation, lipid peroxidation and antioxidant enzyme activities in the aging brain. J Neural Transm 108(8–9):955–967PubMedCrossRefGoogle Scholar
  13. 13.
    Baek BS, Kwon HJ, Lee KH, Yoo MA, Kim KW, Ikeno Y, Yu BP, Chung HY (1999) Regional difference of ROS generation, lipid peroxidation, and antioxidant enzyme activity in rat brain and their dietary modulation. Arch Pharm Res 4:361–366CrossRefGoogle Scholar
  14. 14.
    Butterfield DA, Howard B, Yatin S, Koppal T, Drake J, Hensley K, Aksenov M, Aksenova M, Subramaniam R, Varadarajan S et al (1999) Elevated oxidative stress in models of normal brain aging and Alzheimer’s disease. Life Sci 65(18–19):1883–1892PubMedCrossRefGoogle Scholar
  15. 15.
    Gilmer LK, Ansari MA, Roberts KN, Scheff SW (2010) Age-related changes in mitochondrial respiration and oxidative damage in the cerebral cortex of the Fischer 344 rat. Mech Ageing Dev 2:133–143CrossRefGoogle Scholar
  16. 16.
    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 329635Google Scholar
  17. 17.
    Manczak M, Jung Y, Park BS, Partovi D, Reddy PH (2005) Time-course of mitochondrial gene expressions in mice brains: implications for mitochondrial dysfunction, oxidative damage, and cytochrome c in aging. J Neurochem 3:494–504CrossRefGoogle Scholar
  18. 18.
    Kushnareva Y, Murphy AN, Andreyev A (2002) Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation-reduction state. Biochem J (Pt 2): 45-553Google Scholar
  19. 19.
    Andreyev AI, Kushnareva YE, Starkov AA (2005) Mitochondrial metabolism of reactive oxygen species. Biochemistry 2:200–214Google Scholar
  20. 20.
    Brown GC, Borutaite V (2004) Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols. Biochim Biophys Acta 1658(1–2):44–49PubMedGoogle Scholar
  21. 21.
    Blalock EM, Chen KC, Sharrow K, Herman JP, Porter NM, Foster TC, Landfield PW (2003) Gene Microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J Neurosci 9:3807–3819Google Scholar
  22. 22.
    Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA (2004) Gene regulation and DNA damage in the ageing human brain. Nature 6994:883–891CrossRefGoogle Scholar
  23. 23.
    Dencher NA, Frenzel M, Reifschneider NH, Sugawa M, Krause F (2007) Proteome alterations in rat mitochondria caused by aging. Ann NY Acad Sci 291–298Google Scholar
  24. 24.
    Frenzel M, Rommelspacher H, Sugawa MD, Dencher NA (2010) Ageing alters the supramolecular architecture of OxPhos complexes in rat brain cortex. Exp Gerontol 45(7–8):563–572PubMedCrossRefGoogle Scholar
  25. 25.
    Leuner K, Hauptmann S, Abdel-Kader R, Scherping I, Keil U, Strosznajder JB, Eckert A, Muller WE (2007) Mitochondrial dysfunction: the first domino in brain aging and Alzheimer’s disease? Antioxid Redox Signal 10:1659–1675CrossRefGoogle Scholar
  26. 26.
    Cocco T, Pacelli C, Sgobbo P, Villani G (2009) Control of OXPHOS efficiency by complex I in brain mitochondria. Neurobiol Aging 4:622–629CrossRefGoogle Scholar
  27. 27.
    Cocco T, Sgobbo P, Clemente M, Lopriore B, Grattagliano I, Di Paola M, Villani G (2005) Tissue-specific changes of mitochondrial functions in aged rats: effect of a long-term dietary treatment with N-acetylcysteine. Free Radic Biol Med 6:796–805CrossRefGoogle Scholar
  28. 28.
    Pagani L, Eckert A (2011) Amyloid-Beta interaction with mitochondria. Int J Alzheimers Dis 925050Google Scholar
  29. 29.
    Swerdlow RH (2011) Brain aging, Alzheimer’s disease, and mitochondria. Biochim Biophys Acta 12:1630–1639Google Scholar
  30. 30.
    Santos RX, Correia SC, Wang X, Perry G, Smith MA, Moreira PI, Zhu X (2010) A synergistic dysfunction of mitochondrial fission/fusion dynamics and mitophagy in Alzheimer’s disease. J Alzheimers Dis S401–S412Google Scholar
  31. 31.
    Tabaton M, Tamagno E (2007) The molecular link between beta- and gamma-secretase activity on the amyloid beta precursor protein. Cell Mol Life Sci 17:2211–2218CrossRefGoogle Scholar
  32. 32.
    Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A, Danni O, Smith MA et al (2005) Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem 3:628–636CrossRefGoogle Scholar
  33. 33.
    Gwon AR, Park JS, Arumugam TV, Kwon YK, Chan SL, Kim SH, Baik SH, Yang S, Yun YK, Choi Y et al (2012) Oxidative lipid modification of nicastrin enhances amyloidogenic gamma-secretase activity in Alzheimer’s disease. Aging CellGoogle Scholar
  34. 34.
    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 16:1421–1433PubMedCrossRefGoogle Scholar
  35. 35.
    Kruse SE, Watt WC, Marcinek DJ, Kapur RP, Schenkman KA, Palmiter RD (2008) Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab 4:312–320CrossRefGoogle Scholar
  36. 36.
    Chen L, Yoo SE, Na R, Liu Y, Ran Q (2012) Cognitive impairment and increased Abeta levels induced by paraquat exposure are attenuated by enhanced removal of mitochondrial H(2)O(2). Neurobiol Aging 2:432–26Google Scholar
  37. 37.
    Imanishi H, Yokota M, Mori M, Shimizu A, Nakada K, Hayashi J (2011) Nuclear but not mitochondrial DNA involvement in respiratory complex I defects found in senescence-accelerated mouse strain, SAMP8. Exp Anim 4:397–404CrossRefGoogle Scholar
  38. 38.
    Poon HF, Joshi G, Sultana R, Farr SA, Banks WA, Morley JE, Calabrese V, Butterfield DA (2004) Antisense directed at the A beta region of APP decreases brain oxidative markers in aged senescence accelerated mice. Brain Res 1:86–96CrossRefGoogle Scholar
  39. 39.
    Jellinger KA (2011) Interaction between alpha-synuclein and other proteins in neurodegenerative disorders. Scientific World Journal 1893–1907Google Scholar
  40. 40.
    Jucker M, Walker LC (2011) Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 4:532–540CrossRefGoogle Scholar
  41. 41.
    Kazmierczak A, Strosznajder JB, Adamczyk A (2008) Alpha-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells. Neurochem Int 53(6–8):263–269PubMedCrossRefGoogle Scholar
  42. 42.
    Perluigi M, Butterfield DA (2012) Oxidative stress and Down syndrome: a route toward Alzheimer-like dementia. Curr Gerontol Geriatr Res 724904Google Scholar
  43. 43.
    Bush A, Beail N (2004) Risk factors for dementia in people with down syndrome: issues in assessment and diagnosis. Am J Ment Retard 2:83–97CrossRefGoogle Scholar
  44. 44.
    Zana M, Janka Z, Kalman J (2007) Oxidative stress: a bridge between Down’s syndrome and Alzheimer’s disease. Neurobiol Aging 5:648–676CrossRefGoogle Scholar
  45. 45.
    Bambrick LL, Fiskum G (2008) Mitochondrial dysfunction in mouse trisomy 16 brain. Brain Res 9–16Google Scholar
  46. 46.
    Valenti D, Manente GA, Moro L, Marra E, Vacca RA (2011) Deficit of complex I activity in human skin fibroblasts with chromosome 21 trisomy and overproduction of reactive oxygen species by mitochondria: involvement of the cAMP/PKA signalling pathway. Biochem J 3:679–688CrossRefGoogle Scholar
  47. 47.
    Guglielmotto M, Aragno M, Autelli R, Giliberto L, Novo E, Colombatto S, Danni O, Parola M, Smith MA, Perry G et al (2009) The upregulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1alpha. J Neurochem 4:1045–1056CrossRefGoogle Scholar
  48. 48.
    Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE, Song W (2006) Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci U S A 49:18727–18732CrossRefGoogle Scholar
  49. 49.
    Zhang X, Zhou K, Wang R, Cui J, Lipton SA, Liao FF, Xu H, Zhang YW (2007) Hypoxia-inducible factor 1alpha (HIF-1alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation. J Biol Chem 15:10873–10880CrossRefGoogle Scholar
  50. 50.
    Bell EL, Klimova TA, Eisenbart J, Moraes CT, Murphy MP, Budinger GR, Chandel NS (2007) The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production. J Cell Biol 6:1029–1036CrossRefGoogle Scholar
  51. 51.
    Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA (2004) Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology 7:1148–1155CrossRefGoogle Scholar
  52. 52.
    Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA (2009) The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol 2:200–208CrossRefGoogle Scholar
  53. 53.
    Chen HK, Ji ZS, Dodson SE, Miranda RD, Rosenblum CI, Reynolds IJ, Freedman SB, Weisgraber KH, Huang Y, Mahley RW (2011) Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease. J Biol Chem 7:5215–5221CrossRefGoogle Scholar
  54. 54.
    Guglielmotto M, Monteleone D, Giliberto L, Fornaro M, Borghi R, Tamagno E, Tabaton M (2011) Amyloid-beta activates the expression of BACE1 through the JNK pathway. J Alzheimers Dis 4:871–883Google Scholar
  55. 55.
    Buggia-Prevot V, Sevalle J, Rossner S, Checler F (2008) NFkappaB-dependent control of BACE1 promoter transactivation by Abeta42. J Biol Chem 15:10037–10047CrossRefGoogle Scholar
  56. 56.
    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
  57. 57.
    Eckert A, Hauptmann S, Scherping I, Rhein V, Muller-Spahn F, Gotz J, Muller WE (2008) Soluble beta-amyloid leads to mitochondrial defects in amyloid precursor protein and tau transgenic mice. Neurodegener Dis 5(3–4):157–159PubMedCrossRefGoogle Scholar
  58. 58.
    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
  59. 59.
    Eckert A, Hauptmann S, Scherping I, Meinhardt J, Rhein V, Drose S, Brandt U, Fandrich M, Muller WE, Gotz J (2008) Oligomeric and fibrillar species of beta-amyloid (A beta 42) both impair mitochondrial function in P301L tau transgenic mice. J Mol Med (Berl) 11:1255–1267CrossRefGoogle Scholar
  60. 60.
    Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 34:14670–14675CrossRefGoogle Scholar
  61. 61.
    Gillardon F, Rist W, Kussmaul L, Vogel J, Berg M, Danzer K, Kraut N, Hengerer B (2007) Proteomic and functional alterations in brain mitochondria from Tg2576 mice occur before amyloid plaque deposition. Proteomics 4:605–616CrossRefGoogle Scholar
  62. 62.
    Fu YJ, Xiong S, Lovell MA, Lynn BC (2009) Quantitative proteomic analysis of mitochondria in aging PS-1 transgenic mice. Cell Mol Neurobiol 5:649–664CrossRefGoogle Scholar
  63. 63.
    Hansson Petersen CA, Alikhani N, Behbahani H, Wiehager B, Pavlov PF, Alafuzoff I, Leinonen V, Ito A, Winblad B, Glaser E et al (2008) The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci U S A 35:13145–13150CrossRefGoogle Scholar
  64. 64.
    Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M et al (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 5669:448–452CrossRefGoogle Scholar
  65. 65.
    Hansson CA, Frykman S, Farmery MR, Tjernberg LO, Nilsberth C, Pursglove SE, Ito A, Winblad B, Cowburn RF, Thyberg J et al (2004) Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. J Biol Chem 49:51654–51660CrossRefGoogle Scholar
  66. 66.
    Falkevall A, Alikhani N, Bhushan S, Pavlov PF, Busch K, Johnson KA, Eneqvist T, Tjernberg L, Ankarcrona M, Glaser E (2006) Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP. J Biol Chem 39:29096–29104CrossRefGoogle Scholar
  67. 67.
    Alikhani N, Guo L, Yan S, Du H, Pinho CM, Chen JX, Glaser E, Yan SS (2011) Decreased proteolytic activity of the mitochondrial amyloid-beta degrading enzyme, PreP peptidasome, in Alzheimer’s disease brain mitochondria. J Alzheimers Dis 1:75–87Google Scholar
  68. 68.
    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
  69. 69.
    Fukui H, Diaz F, Garcia S, Moraes CT (2007) 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 U S A 35:14163–14168CrossRefGoogle Scholar
  70. 70.
    Pickrell AM, Fukui H, Moraes CT (2009) The role of cytochrome c oxidase deficiency in ROS and amyloid plaque formation. J Bioenerg Biomembr 5:453–456CrossRefGoogle Scholar
  71. 71.
    Finsterer J (2009) Mitochondrial disorders, cognitive impairment and dementia. J Neurol Sci 283(1–2):143–148PubMedCrossRefGoogle Scholar
  72. 72.
    Salsano E, Giovagnoli AR, Morandi L, Maccagnano C, Lamantea E, Marchesi C, Zeviani M, Pareyson D (2011) Mitochondrial dementia: a sporadic case of progressive cognitive and behavioral decline with hearing loss due to the rare m.3291T>C MELAS mutation. J Neurol Sci 300(1–2):165–168PubMedCrossRefGoogle Scholar
  73. 73.
    Kaido M, Fujimura H, Soga F, Toyooka K, Yoshikawa H, Nishimura T, Higashi T, Inui K, Imanishi H, Yorifuji S et al (1996) Alzheimer-type pathology in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Acta Neuropathol 3:312–318CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Kristina Leuner
    • 1
    Email author
  • Walter E. Müller
    • 2
  • Andreas S. Reichert
    • 3
  1. 1.Molecular and Clinical PharmacyFAU Erlangen/NürnbergErlangenGermany
  2. 2.Department of Pharmacology, Biocenter NiederurselGoethe University Frankfurt am MainFrankfurt am MainGermany
  3. 3.Mitochondrial Biology, Buchmann Institute for Molecular Life SciencesGoethe University Frankfurt am Main, Fachbereich MedizinFrankfurt am MainGermany

Personalised recommendations