Abstract
Although great advances have been made in our understanding of the neurodegenerative process in Alzheimer’s disease (AD), the complete picture has not emerged and there are still pieces missing. One attractive hypothesis is that mitochondrial failure is a cause of synapse loss and cognitive impairment in AD. ATP generation by mitochondria is crucial for proper synaptic function and therefore neurons are highly sensitive to mitochondrial damage potentially leading to synapse loss and cognitive dysfunction. Several evidences indicate that mitochondria are indeed damaged and dysfunctional in the AD brain; these include mitochondrial accumulation of amyloid β-peptide (Aβ), impaired brain glucose metabolism, impaired mitochondrial fusion/fission, and increased generation of reactive oxygen species (ROS). In this chapter we will focus on the role of Aβ in mitochondria and discuss mitochondrial uptake mechanisms and interactions with mitochondrial proteins. Several evidences point towards a central role of Aβ initiating mitochondrial damage and generation of ROS in turn leading to synaptic and neuronal degeneration. Therefore, it would be of high importance to develop drugs that maintain mitochondrial integrity and prevent mitochondrial failure otherwise leading neuronal dysfunction.
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References
Swerdlow RH, Khan SM. A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med Hypotheses. 2004;63:8–20.
Selkoe DJ. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res. 2008;192:106–13.
Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, et al. Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci. 2011;31:6627–38.
Crouch PJ, Blake R, Duce JA, Ciccotosto GD, Li QX, et al. Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1-42. J Neurosci. 2005;25:672–9.
Caspersen C, Wang N, Yao J, Sosunov A, Chen X, et al. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. FASEB J. 2005;19:2040–1.
Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, et al. Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet. 2006;15:1437–49.
Hansson Petersen CA, Alikhani N, Behbahani H, Wiehager B, Pavlov PF, et al. 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. 2008;105:13145–50.
Du H, Guo L, Yan S, Sosunov AA, McKhann GM, et al. Early deficits in synaptic mitochondria in an Alzheimer’s disease mouse model. Proc Natl Acad Sci U S A. 2010;107:18670–5.
Dragicevic N, Mamcarz M, Zhu Y, Buzzeo R, Tan J, et al. Mitochondrial amyloid-beta levels are associated with the extent of mitochondrial dysfunction in different brain regions and the degree of cognitive impairment in Alzheimer’s transgenic mice. J Alzheimers Dis. 2010;20 Suppl 2:S535–50.
Bergmans BA, De Strooper B. Gamma-secretases: from cell biology to therapeutic strategies. Lancet Neurol. 2010;9:215–26.
Benilova I, Karran E, De Strooper B. The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci. 2012;15:349–57.
Anandatheerthavarada HK, Biswas G, Robin MA, Avadhani NG. 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.
Hansson CA, Frykman S, Farmery MR, Tjernberg LO, Nilsberth C, et al. Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. J Biol Chem. 2004;279:51654–60.
Devi L, Prabhu BM, Galati DF, Avadhani NG, Anandatheerthavarada HK. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J Neurosci. 2006;26:9057–68.
Pavlov PF, Wiehager B, Sakai J, Frykman S, Behbahani H, et al. Mitochondrial gamma-secretase participates in the metabolism of mitochondria-associated amyloid precursor protein. FASEB J. 2011;25:78–88.
Muresan V, Varvel NH, Lamb BT, Muresan Z. The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites. J Neurosci. 2009;29:3565–78.
Area-Gomez E, de Groof AJ, Boldogh I, Bird TD, Gibson GE, et al. Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am J Pathol. 2009;175:1810–6.
Schon EA, Area-Gomez E. Is Alzheimer’s disease a disorder of mitochondria-associated membranes? J Alzheimers Dis. 2010;20 Suppl 2:S281–92.
Singh P, Suman S, Chandna S, Das TK. Possible role of amyloid-beta, adenine nucleotide translocase and cyclophilin-D interaction in mitochondrial dysfunction of Alzheimer’s disease. Bioinformation. 2009;3:440–5.
Roses AD, Lutz MW, Amrine-Madsen H, Saunders AM, Crenshaw DG, et al. A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer’s disease. Pharmacogenomics J. 2010;10(5):375–84.
Hedskog L, Brohede J, Wiehager B, Pinho CM, Revathikumar P, Lilius L, et al. Biochemical studies of poly-T variants in the Alzheimer’s disease associated TOMM40 gene. J Alzheimers Dis. 2012;31:527–36.
Pagani L, Eckert A. Amyloid-Beta interaction with mitochondria. Int J Alzheimers Dis. 2011;2011:925050.
Maurer I, Zierz S, Moller HJ. A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol Aging. 2000;21:455–62.
Cottrell DA, Blakely EL, Johnson MA, Ince PG, Turnbull DM. Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD. Neurology. 2001;57:260–4.
Cottrell DA, Borthwick GM, Johnson MA, Ince PG, Turnbull DM. The role of cytochrome c oxidase deficient hippocampal neurones in Alzheimer’s disease. Neuropathol Appl Neurobiol. 2002;28:390–6.
Cardoso SM, Santana I, Swerdlow RH, Oliveira CR. Mitochondria dysfunction of Alzheimer’s disease cybrids enhances Abeta toxicity. J Neurochem. 2004;89:1417–26.
Cardoso SM, Proenca MT, Santos S, Santana I, Oliveira CR. Cytochrome c oxidase is decreased in Alzheimer’s disease platelets. Neurobiol Aging. 2004;25:105–10.
Canevari L, Clark JB, Bates TE. beta-Amyloid fragment 25–35 selectively decreases complex IV activity in isolated mitochondria. FEBS Lett. 1999;457:131–4.
Casley CS, Canevari L, Land JM, Clark JB, Sharpe MA. Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J Neurochem. 2002;80:91–100.
Parks JK, Smith TS, Trimmer PA, Bennett Jr JP, Parker Jr WD. Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro. J Neurochem. 2001;76:1050–6.
Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, et al. Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2009;106:14670–5.
Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, et al. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci U S A. 2009;106:20057–62.
Miura T, Tanno M. The mPTP and its regulatory proteins: final common targets of signalling pathways for protection against necrosis. Cardiovasc Res. 2012;94:181–9.
Du H, Guo L, Fang F, Chen D, Sosunov AA, et al. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med. 2008;14:1097–105.
Du H, Guo L, Zhang W, Rydzewska M, Yan S. Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model. Neurobiol Aging. 2011;32(3):398–406.
Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science. 2004;304:448–52.
Takuma K, Yao J, Huang J, Xu H, Chen X, et al. ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB J. 2005;19:597–8.
Yan Y, Liu Y, Sorci M, Belfort G, Lustbader JW, et al. Surface plasmon resonance and nuclear magnetic resonance studies of ABAD-Abeta interaction. Biochemistry. 2007;46:1724–31.
Yao J, Du H, Yan S, Fang F, Wang C, et al. Inhibition of amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase-Abeta interaction reduces Abeta accumulation and improves mitochondrial function in a mouse model of Alzheimer’s disease. J Neurosci. 2011;31:2313–20.
Falkevall A, Alikhani N, Bhushan S, Pavlov PF, Busch K, Johnson KA, Eneqvist T, Tjernberg L, Ankarcrona M, Glaser E. Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP. J Biol Chem. 2006;281:29096–104.
Stahl A, Moberg P, Ytterberg J, Panfilov O, Brockenhuus Von Lowenhielm H, et al. Isolation and identification of a novel mitochondrial metalloprotease (PreP) that degrades targeting presequences in plants. J Biol Chem. 2002;277:41931–9.
Moberg P, Stahl A, Bhushan S, Wright SJ, Eriksson A, et al. Characterization of a novel zinc metalloprotease involved in degrading targeting peptides in mitochondria and chloroplasts. Plant J. 2003;36:616–28.
Stahl A, Nilsson S, Lundberg P, Bhushan S, Biverstahl H, et al. Two novel targeting peptide degrading proteases, PrePs, in mitochondria and chloroplasts, so similar and still different. J Mol Biol. 2005;349:847–60.
Kurochkin IV. Insulin-degrading enzyme: embarking on amyloid destruction. Trends Biochem Sci. 2001;26:421–5.
Selkoe DJ. Clearing the brain’s amyloid cobwebs. Neuron. 2001;32:177–80.
Tanzi RE, Moir RD, Wagner SL. Clearance of Alzheimer’s Abeta peptide: the many roads to perdition. Neuron. 2004;43:605–8.
Alikhani N, Guo L, Yan S, Du H, Pinho CM, et al. Decreased proteolytic activity of the mitochondrial amyloid-beta degrading enzyme, PreP peptidasome, in Alzheimer’s disease brain mitochondria. J Alzheimers Dis. 2011;27:75–87.
Shinall H, Song ES, Hersh LB. Susceptibility of amyloid beta peptide degrading enzymes to oxidative damage: a potential Alzheimer’s disease spiral. Biochemistry. 2005;44:15345–50.
Leuner K, Schutt T, Kurz C, Eckert SH, Schiller C, et al. Mitochondrion-derived reactive oxygen species lead to enhanced amyloid Beta formation. Antioxid Redox Signal. 2012;16:1421–33.
McManus MJ, Murphy MP, Franklin JL. The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease. J Neurosci. 2011;31:15703–15.
Snow BJ, Rolfe FL, Lockhart MM, Frampton CM, O’Sullivan JD, et al. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson’s disease. Mov Disord. 2010;25:1670–4.
Ankarcrona M, Mangialasche F, Winblad B. Rethinking Alzheimer’s disease therapy: are mitochondria the key? J Alzheimers Dis. 2010;20 Suppl 2:S579–90.
Matveeva IA. Action of dimebon on histamine receptors. Farmakol Toksikol. 1983;46:27–9.
Lermontova NN, Lukoyanov NV, Serkova TP, Lukoyanova EA, Bachurin SO. Dimebon improves learning in animals with experimental Alzheimer’s disease. Bull Exp Biol Med. 2000;129:544–6.
Bachurin S, Bukatina E, Lermontova N, Tkachenko S, Afanasiev A, et al. Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci. 2001;939:425–35.
Wu J, Li Q, Bezprozvanny I. Evaluation of Dimebon in cellular model of Huntington’s disease. Mol Neurodegener. 2008;3:15.
Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, et al. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study. Lancet. 2008;372:207–15.
www.clinicaltrial.gov Accessed 17 May 2012.
Schaffhauser H, Mathiasen JR, Dicamillo A, Huffman MJ, Lu LD, et al. Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities. Biochem Pharmacol. 2009;78:1035–42.
Grigorev VV, Dranyi OA, Bachurin SO. Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull Exp Biol Med. 2003;136:474–7.
Lermontova NN, Redkozubov AE, Shevtsova EF, Serkova TP, Kireeva EG, et al. Dimebon and tacrine inhibit neurotoxic action of beta-amyloid in culture and block l-type Ca(2+) channels. Bull Exp Biol Med. 2001;132:1079–83.
Bachurin SO, Shevtsova EP, Kireeva EG, Oxenkrug GF, Sablin SO. Mitochondria as a target for neurotoxins and neuroprotective agents. Ann N Y Acad Sci. 2003;993:334–44. discussion 345–339.
Zhang S, Hedskog L, Petersen CA, Winblad B, Ankarcrona M. Dimebon (latrepirdine) enhances mitochondrial function and protects neuronal cells from death. J Alzheimers Dis. 2010;21:389–402.
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Ankarcrona, M. (2013). Aβ in Mitochondria—One Piece in the Alzheimer’s Disease Puzzle. In: Praticὸ, D., Mecocci, P. (eds) Studies on Alzheimer's Disease. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-598-9_5
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DOI: https://doi.org/10.1007/978-1-62703-598-9_5
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