Abstract
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.
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Qiu C, Kivipelto M, von Strauss E (2009) Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci 2:111–128
Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 4:329–344
Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 2:101–112
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 10:1659–1675
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 11:1359–1370
Starkov AA (2008) The role of mitochondria in reactive oxygen species metabolism and signaling. Ann NY Acad Sci 37–52
Drose S, Brandt U (2008) The mechanism of mitochondrial superoxide production by the cytochrome bc1 complex. J Biol Chem 31:21649–21654
Mattson MP, Magnus T (2006) Ageing and neuronal vulnerability. Nat Rev Neurosci 4:278–294
Scherz-Shouval R, Elazar Z (2011) Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 1:30–38
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 3:225–227
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 6:312–315
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):955–967
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 4:361–366
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):1883–1892
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 2:133–143
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 329635
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 3:494–504
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): 45-553
Andreyev AI, Kushnareva YE, Starkov AA (2005) Mitochondrial metabolism of reactive oxygen species. Biochemistry 2:200–214
Brown GC, Borutaite V (2004) Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols. Biochim Biophys Acta 1658(1–2):44–49
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 9:3807–3819
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 6994:883–891
Dencher NA, Frenzel M, Reifschneider NH, Sugawa M, Krause F (2007) Proteome alterations in rat mitochondria caused by aging. Ann NY Acad Sci 291–298
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):563–572
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 10:1659–1675
Cocco T, Pacelli C, Sgobbo P, Villani G (2009) Control of OXPHOS efficiency by complex I in brain mitochondria. Neurobiol Aging 4:622–629
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 6:796–805
Pagani L, Eckert A (2011) Amyloid-Beta interaction with mitochondria. Int J Alzheimers Dis 925050
Swerdlow RH (2011) Brain aging, Alzheimer’s disease, and mitochondria. Biochim Biophys Acta 12:1630–1639
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–S412
Tabaton M, Tamagno E (2007) The molecular link between beta- and gamma-secretase activity on the amyloid beta precursor protein. Cell Mol Life Sci 17:2211–2218
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 3:628–636
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 Cell
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 16:1421–1433
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 4:312–320
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 2:432–26
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 4:397–404
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 1:86–96
Jellinger KA (2011) Interaction between alpha-synuclein and other proteins in neurodegenerative disorders. Scientific World Journal 1893–1907
Jucker M, Walker LC (2011) Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 4:532–540
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):263–269
Perluigi M, Butterfield DA (2012) Oxidative stress and Down syndrome: a route toward Alzheimer-like dementia. Curr Gerontol Geriatr Res 724904
Bush A, Beail N (2004) Risk factors for dementia in people with down syndrome: issues in assessment and diagnosis. Am J Ment Retard 2:83–97
Zana M, Janka Z, Kalman J (2007) Oxidative stress: a bridge between Down’s syndrome and Alzheimer’s disease. Neurobiol Aging 5:648–676
Bambrick LL, Fiskum G (2008) Mitochondrial dysfunction in mouse trisomy 16 brain. Brain Res 9–16
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 3:679–688
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 4:1045–1056
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 49:18727–18732
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 15:10873–10880
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 6:1029–1036
Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA (2004) Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology 7:1148–1155
Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA (2009) The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol 2:200–208
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 7:5215–5221
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 4:871–883
Buggia-Prevot V, Sevalle J, Rossner S, Checler F (2008) NFkappaB-dependent control of BACE1 promoter transactivation by Abeta42. J Biol Chem 15:10037–10047
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 10:1574–1586
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):157–159
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 47:20057–20062
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) 11:1255–1267
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 34:14670–14675
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 4:605–616
Fu YJ, Xiong S, Lovell MA, Lynn BC (2009) Quantitative proteomic analysis of mitochondria in aging PS-1 transgenic mice. Cell Mol Neurobiol 5:649–664
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 35:13145–13150
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 5669:448–452
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 49:51654–51660
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 39:29096–29104
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 1:75–87
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 25:23802–23814
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 35:14163–14168
Pickrell AM, Fukui H, Moraes CT (2009) The role of cytochrome c oxidase deficiency in ROS and amyloid plaque formation. J Bioenerg Biomembr 5:453–456
Finsterer J (2009) Mitochondrial disorders, cognitive impairment and dementia. J Neurol Sci 283(1–2):143–148
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):165–168
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 3:312–318
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Leuner, K., Müller, W.E. & Reichert, A.S. From Mitochondrial Dysfunction to Amyloid Beta Formation: Novel Insights into the Pathogenesis of Alzheimer’s Disease. Mol Neurobiol 46, 186–193 (2012). https://doi.org/10.1007/s12035-012-8307-4
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DOI: https://doi.org/10.1007/s12035-012-8307-4