Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that represents the most common form of dementia among the elderly. Despite the fact that AD was studied for decades, the underlying mechanisms that trigger this neuropathology remain unresolved. Since the onset of cognitive deficits occurs generally within the 6th decade of life, except in rare familial case, advancing age is the greatest known risk factor for AD. To unravel the pathogenesis of the disease, numerous studies use cellular and animal models based on genetic mutations found in rare early onset familial AD (FAD) cases that represent less than 1 % of AD patients. However, the underlying process that leads to FAD appears to be distinct from that which results in late-onset AD. As a genetic disorder, FAD clearly is a consequence of malfunctioning/mutated genes, while late-onset AD is more likely due to a gradual accumulation of age-related malfunction. Normal aging and AD are both marked by defects in brain metabolism and increased oxidative stress, albeit to varying degrees. Mitochondria are involved in these two phenomena by controlling cellular bioenergetics and redox homeostasis. In the present review, we compare the common features observed in both brain aging and AD, placing mitochondrial in the center of pathological events that separate normal and pathological aging. We emphasize a bioenergetic model for AD including the inverse Warburg hypothesis which postulates that AD is a consequence of mitochondrial deregulation leading to metabolic reprogramming as an initial attempt to maintain neuronal integrity. After the failure of this compensatory mechanism, bioenergetic deficits may lead to neuronal death and dementia. Thus, mitochondrial dysfunction may represent the missing link between aging and sporadic AD, and represent attractive targets against neurodegeneration.
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References
Adam-Vizi V, Chinopoulos C (2006) Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci 27:639–645. doi:10.1016/j.tips.2006.10.005
Ashby EL, Miners JS, Kumar S, Walter J, Love S, Kehoe PG (2015) Investigation of Abeta phosphorylated at serine 8 (pAbeta) in Alzheimer’s disease, dementia with Lewy bodies and vascular dementia. Neuropathol Appl Neurobiol 41:428–444. doi:10.1111/nan.12212
Benard G, Rossignol R (2008) Ultrastructure of the mitochondrion and its bearing on function and bioenergetics. Antioxid Redox Signal 10:1313–1342. doi:10.1089/ars.2007.2000
Bohr VA (2002) Repair of oxidative DNA damage in nuclear and mitochondrial DNA, and some changes with aging in mammalian cells. Free Radic Biol Med 32:804–812
Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM (2007) Forecasting the global burden of Alzheimer’s disease. Alzheimer’s Dement 3:186–191. doi:10.1016/j.jalz.2007.04.381
Brown GC, Borutaite V (2002) Nitric oxide inhibition of mitochondrial respiration and its role in cell death. Free Radic Biol Med 33:1440–1450
Bu G (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10:333–344. doi:10.1038/nrn2620
Campello S, Scorrano L (2010) Mitochondrial shape changes: orchestrating cell pathophysiology. EMBO Rep 11:678–684. doi:10.1038/embor.2010.115
Castello MA, Soriano S (2014) On the origin of Alzheimer’s disease trials and tribulations of the amyloid hypothesis. Ageing Res Rev 13:10–12. doi:10.1016/j.arr.2013.10.001
Chabrier MA, Blurton-Jones M, Agazaryan AA, Nerhus JL, Martinez-Coria H, LaFerla FM (2012) Soluble abeta promotes wild-type tau pathology in vivo. J Neurosci 32:17345–17350. doi:10.1523/JNEUROSCI.0172-12.2012
Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125:1241–1252. doi:10.1016/j.cell.2006.06.010
Chauhan A, Vera J, Wolkenhauer O (2014) The systems biology of mitochondrial fission and fusion and implications for disease and aging. Biogerontology 15:1–12. doi:10.1007/s10522-013-9474-z
Chen HK et al (2011) Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease. J Biol Chem 286:5215–5221. doi:10.1074/jbc.M110.151084
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 33(432):e415–426. doi:10.1016/j.neurobiolaging.2011.01.008
Cheng XR, Zhou WX, Zhang YX (2014) The behavioral, pathological and therapeutic features of the senescence-accelerated mouse prone 8 strain as an Alzheimer’s disease animal model. Ageing Res Rev 13:13–37. doi:10.1016/j.arr.2013.10.002
Crouch PJ et al (2005) Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1-42. J Neurosci 25:672–679. doi:10.1523/JNEUROSCI.4276-04.2005
David DC et al (2005) Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem 280:23802–23814. doi:10.1074/jbc.M500356200
Demetrius LA, Driver J (2013) Alzheimer’s as a metabolic disease. Biogerontology 14:641–649. doi:10.1007/s10522-013-9479-7
Demetrius LA, Driver JA (2015) Preventing Alzheimer’s disease by means of natural selection. J R Soc Interface 12:20140919
Demetrius LA, Simon DK (2012) An inverse-Warburg effect and the origin of Alzheimer’s disease. Biogerontology 13:583–594. doi:10.1007/s10522-012-9403-6
Demetrius LA, Magistretti PJ, Pellerin L (2014) Alzheimer’s disease: the amyloid hypothesis and the Inverse Warburg effect. Front Physiol 5:522. doi:10.3389/fphys.2014.00522
Drachman DA (2006) Aging of the brain, entropy, and Alzheimer disease. Neurology 67:1340–1352. doi:10.1212/01.wnl.0000240127.89601.83
DuBoff B, Gotz J, Feany MB (2012) Tau promotes neurodegeneration via DRP1 mislocalization in vivo. Neuron 75:618–632. doi:10.1016/j.neuron.2012.06.026
Eckert A et al (2008a) Oligomeric and fibrillar species of beta-amyloid (A beta 42) both impair mitochondrial function in P301L tau transgenic mice. J Mol Med (Berl) 86:1255–1267. doi:10.1007/s00109-008-0391-6
Eckert A, Hauptmann S, Scherping I, Rhein V, Muller-Spahn F, Gotz J, Muller WE (2008b) Soluble beta-amyloid leads to mitochondrial defects in amyloid precursor protein and tau transgenic mice. Neurodegener Dis 5:157–159. doi:10.1159/000113689
Eckert A, Nisbet R, Grimm A, Gotz J (2014) March separate, strike together–role of phosphorylated TAU in mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta 1842:1258–1266. doi:10.1016/j.bbadis.2013.08.013
Ferger AI, Campanelli L, Reimer V, Muth KN, Merdian I, Ludolph AC, Witting A (2010) Effects of mitochondrial dysfunction on the immunological properties of microglia. J Neuroinflammation 7:45. doi:10.1186/1742-2094-7-45
Friedman JR, Nunnari J (2014) Mitochondrial form and function. Nature 505:335–343. doi:10.1038/nature12985
Frost B, Gotz J, Feany MB (2015) Connecting the dots between tau dysfunction and neurodegeneration. Trends Cell Biol 25:46–53. doi:10.1016/j.tcb.2014.07.005
Gillardon F et al (2007) Proteomic and functional alterations in brain mitochondria from Tg2576 mice occur before amyloid plaque deposition. Proteomics 7:605–616. doi:10.1002/pmic.200600728
Giorgio M, Trinei M, Migliaccio E, Pelicci PG (2007) Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? Nat Rev Mol Cell Biol 8:722–728. doi:10.1038/nrm2240
Goedert M, Jakes R (2005) Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta 1739:240–250. doi:10.1016/j.bbadis.2004.08.007
Goldstein S, Merenyi G (2008) The chemistry of peroxynitrite: implications for biological activity. Methods Enzymol 436:49–61. doi:10.1016/S0076-6879(08)36004-2
Gottschalk WK, Lutz MW, He YT, Saunders AM, Burns DK, Roses AD, Chiba-Falek O (2014) The broad impact of TOM40 on neurodegenerative diseases in aging. J Parkinson’s Dis Alzheimer’s Dis 1 doi:10.13188/2376-922X.1000003
Götz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9:532–544. doi:10.1038/nrn2420
Götz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–1495. doi:10.1126/science.1062097
Goure WF, Krafft GA, Jerecic J, Hefti F (2014) Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer’s disease immunotherapeutics. Alzheimers Res Ther 6:42. doi:10.1186/alzrt272
Grimm A, Biliouris EE, Lang UE, Gotz J, Mensah-Nyagan AG, Eckert A (2015) Sex hormone-related neurosteroids differentially rescue bioenergetic deficits induced by amyloid-beta or hyperphosphorylated tau protein. Cel Mol Life Sci. doi:10.1007/s00018-015-1988-x
Guglielmotto M et al (2009) The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1alpha. J Neurochem 108:1045–1056. doi:10.1111/j.1471-4159.2008.05858.x
Guillozet AL, Weintraub S, Mash DC, Mesulam MM (2003) Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 60:729–736. doi:10.1001/archneur.60.5.729
Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185
Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300
Harper ME, Bevilacqua L, Hagopian K, Weindruch R, Ramsey JJ (2004) Ageing, oxidative stress, and mitochondrial uncoupling. Acta Physiol Scand 182:321–331. doi:10.1111/j.1365-201X.2004.01370.x
Hauptmann S et al (2009) Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging 30:1574–1586. doi:10.1016/j.neurobiolaging.2007.12.005
Hayflick L (2007) Entropy explains aging, genetic determinism explains longevity, and undefined terminology explains misunderstanding both. PLoS Genet 3:e220. doi:10.1371/journal.pgen.0030220
Herrup K (2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18:794–799. doi:10.1038/nn.4017
Hunter RL et al (2007) Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem 100:1375–1386. doi:10.1111/j.1471-4159.2006.04327.x
Hyun DH et al (2010) The plasma membrane redox system is impaired by amyloid beta-peptide and in the hippocampus and cerebral cortex of 3xTgAD mice. Exp Neurol 225:423–429. doi:10.1016/j.expneurol.2010.07.020
Ishihara Y et al (2013) Involvement of brain oxidation in the cognitive impairment in a triple transgenic mouse model of Alzheimer’s disease: noninvasive measurement of the brain redox state by magnetic resonance imaging. Free Radic Res 47:731–739. doi:10.3109/10715762.2013.818218
Jezek P, Hlavata L (2005) Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. Int J Biochem Cell Biol 37:2478–2503. doi:10.1016/j.biocel.2005.05.013
Kalous M, Drahota Z (1996) The role of mitochondria in aging. Physiol Res 45:351–359
Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:698–712. doi:10.1038/nrd3505
Keil U et al (2004) Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem 279:50310–50320. doi:10.1074/jbc.M405600200
Kishida KT, Klann E (2007) Sources and targets of reactive oxygen species in synaptic plasticity and memory. Antioxid Redox Signal 9:233–244. doi:10.1089/ars.2007.9.ft-8
Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9:505–518. doi:10.1038/nrn2417
Kurokawa T, Asada S, Nishitani S, Hazeki O (2001) Age-related changes in manganese superoxide dismutase activity in the cerebral cortex of senescence-accelerated prone and resistant mouse. Neurosci Lett 298:135–138
LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 8:499–509. doi:10.1038/nrn2168
Lee HC, Wei YH (1997) Mutation and oxidative damage of mitochondrial DNA and defective turnover of mitochondria in human aging. J Formos Med Assoc 96:770–778
Leuner K, Muller WE, Reichert AS (2012a) From mitochondrial dysfunction to amyloid beta formation: novel insights into the pathogenesis of Alzheimer’s disease. Mol Neurobiol 46:186–193. doi:10.1007/s12035-012-8307-4
Leuner K et al (2012b) Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation. Antioxid Redox Signal 16:1421–1433. doi:10.1089/ars.2011.4173
Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9:106–118. doi:10.1038/nrneurol.2012.263
Lopez-Gonzalez I et al (2015) Neuroinflammatory signals in Alzheimer disease and APP/PS1 transgenic mice: correlations with plaques, tangles, and oligomeric species. J Neuropathol Exp Neurol 74:319–344. doi:10.1097/NEN.0000000000000176
Lyall DM et al (2014) Alzheimer’s disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936. Neurobiol Aging 35(1513):e1525–1533. doi:10.1016/j.neurobiolaging.2014.01.006
Manczak M, Reddy PH (2012) Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer’s disease neurons: implications for mitochondrial dysfunction and neuronal damage. Hum Mol Genet 21:2538–2547. doi:10.1093/hmg/dds072
Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631–639. doi:10.1038/nature02621
Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60:748–766. doi:10.1016/j.neuron.2008.10.010
McManus MJ, Murphy MP, Franklin JL (2011) 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 31:15703–15715. doi:10.1523/JNEUROSCI.0552-11.2011
Melov S et al (2007) Mitochondrial oxidative stress causes hyperphosphorylation of tau. PLoS One 2:e536. doi:10.1371/journal.pone.0000536
Morris GP, Clark IA, Vissel B (2014) Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta Neuropathol Commun 2:135. doi:10.1186/s40478-014-0135-5
Nagy Z, Esiri MM, LeGris M, Matthews PM (1999) Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology. Acta Neuropathol 97:346–354
Nakamura T, Watanabe A, Fujino T, Hosono T, Michikawa M (2009) Apolipoprotein E4 (1-272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells. Mol Neurodegener 4:35. doi:10.1186/1750-1326-4-35
Navarro A, Boveris A (2004) Rat brain and liver mitochondria develop oxidative stress and lose enzymatic activities on aging. Am J of Physiol Regul Integr Comp Physiol 287:R1244–R1249. doi:10.1152/ajpregu.00226.2004
Nelson PT et al (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381. doi:10.1097/NEN.0b013e31825018f7
Perry G, Nunomura A, Hirai K, Takeda A, Aliev G, Smith MA (2000) Oxidative damage in Alzheimer’s disease: the metabolic dimension. Int J Dev Neurosci 18:417–421
Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimer’s Dement 9(63–75):e62. doi:10.1016/j.jalz.2012.11.007
Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344. doi:10.1056/NEJMra0909142
Raichle ME, Gusnard DA (2002) Appraising the brain’s energy budget. Proc Natl Acad Sci USA 99:10237–10239. doi:10.1073/pnas.172399499
Rebrin I, Forster MJ, Sohal RS (2007) Effects of age and caloric intake on glutathione redox state in different brain regions of C57BL/6 and DBA/2 mice. Brain Res 1127:10–18. doi:10.1016/j.brainres.2006.10.040
Reddy PH et al (2004) Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer’s disease. Hum Mol Genet 13:1225–1240. doi:10.1093/hmg/ddh140
Reitz C, Mayeux R (2014) Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 88:640–651. doi:10.1016/j.bcp.2013.12.024
Resende R, Moreira PI, Proenca T, Deshpande A, Busciglio J, Pereira C, Oliveira CR (2008) Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radic Biol Med 44:2051–2057. doi:10.1016/j.freeradbiomed.2008.03.012
Rhein V, Baysang G, Rao S, Meier F, Bonert A, Muller-Spahn F, Eckert A (2009a) Amyloid-beta leads to impaired cellular respiration, energy production and mitochondrial electron chain complex activities in human neuroblastoma cells. Cell Mol Neurobiol 29:1063–1071. doi:10.1007/s10571-009-9398-y
Rhein V et al (2009b) Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci USA 106:20057–20062. doi:10.1073/pnas.0905529106
Rhein V et al (2010) Ginkgo biloba extract ameliorates oxidative phosphorylation performance and rescues abeta-induced failure. PLoS One 5:e12359. doi:10.1371/journal.pone.0012359
Richards JG et al (2003) PS2APP transgenic mice, coexpressing hPS2mut and hAPPswe, show age-related cognitive deficits associated with discrete brain amyloid deposition and inflammation. J Neurosci 23:8989–9003
Roses AD et al (2010) A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer’s disease. Pharmacogenomics J 10:375–384. doi:10.1038/tpj.2009.69
Scheffler IE (2001) A century of mitochondrial research: achievements and perspectives. Mitochondrion 1:3–31
Schmitt K, Grimm A, Kazmierczak A, Strosznajder JB, Götz J, Eckert A (2012) Insights into mitochondrial dysfunction: aging, amyloid-beta, and tau-A deleterious trio. Antioxid Redox Signal 16:1456–1466. doi:10.1089/ars.2011.4400
Schulz KL et al (2012) A new link to mitochondrial impairment in tauopathies. Mol Neurobiol 46:205–216. doi:10.1007/s12035-012-8308-3
Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48:158–167. doi:10.1016/j.molcel.2012.09.025
Seo AY, Joseph AM, Dutta D, Hwang JC, Aris JP, Leeuwenburgh C (2010) New insights into the role of mitochondria in aging: mitochondrial dynamics and more. J Cell Sci 123:2533–2542. doi:10.1242/jcs.070490
Shi C, Xiao S, Liu J, Guo K, Wu F, Yew DT, Xu J (2010) Ginkgo biloba extract EGb761 protects against aging-associated mitochondrial dysfunction in platelets and hippocampi of SAMP8 mice. Platelets 21:373–379. doi:10.3109/09537100903511448
Stauch KL, Purnell PR, Fox HS (2014) Aging synaptic mitochondria exhibit dynamic proteomic changes while maintaining bioenergetic function. Aging 6:320–334
Stockburger C, Gold VA, Pallas T, Kolesova N, Miano D, Leuner K, Muller WE (2014) A cell model for the initial phase of sporadic Alzheimer’s disease. J Alzheimers Dis 42:395–411. doi:10.3233/JAD-140381
Swerdlow RH (2011) Brain aging, Alzheimer’s disease, and mitochondria. Biochim Biophys Acta 1812:1630–1639. doi:10.1016/j.bbadis.2011.08.012
Swerdlow RH, Khan SM (2004) A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med Hypotheses 63:8–20. doi:10.1016/j.mehy.2003.12.045
Swerdlow RH, Burns JM, Khan SM (2014) The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta 1842:1219–1231. doi:10.1016/j.bbadis.2013.09.010
Tamagno E et al (2005) Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem 92:628–636. doi:10.1111/j.1471-4159.2004.02895.x
Tamagno E et al (2008) Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. J Neurochem 104:683–695. doi:10.1111/j.1471-4159.2007.05072.x
Trinczek B, Biernat J, Baumann K, Mandelkow EM, Mandelkow E (1995) Domains of tau protein, differential phosphorylation, and dynamic instability of microtubules. Mol Biol Cell 6:1887–1902
Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344. doi:10.1113/jphysiol.2003.049478
Twig G et al (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446. doi:10.1038/sj.emboj.7601963
Van Dam D, De Deyn PP (2006) Drug discovery in dementia: the role of rodent models. Nat Rev Drug Discov 5:956–970. doi:10.1038/nrd2075
Veal EA, Day AM, Morgan BA (2007) Hydrogen peroxide sensing and signaling. Mol Cell 26:1–14. doi:10.1016/j.molcel.2007.03.016
Vest RS, Pike CJ (2013) Gender, sex steroid hormones, and Alzheimer’s disease. Horm Behav 63:301–307. doi:10.1016/j.yhbeh.2012.04.006
Vina J, Borras C (2010) Women live longer than men: understanding molecular mechanisms offers opportunities to intervene by using estrogenic compounds. Antioxid Redox Signal 13:269–278. doi:10.1089/ars.2009.2952
Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407. doi:10.1146/annurev.genet.39.110304.095751
Wallace DC (2011) Bioenergetic origins of complexity and disease. Cold Spring Harb Symp Quant Biol 76:1–16. doi:10.1101/sqb.2011.76.010462
Walsh DM et al (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539. doi:10.1038/416535a
Wang X, Su B, Fujioka H, Zhu X (2008a) Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer’s disease patients. Am J Pathol 173:470–482. doi:10.2353/ajpath.2008.071208
Wang X et al (2008b) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 105:19318–19323. doi:10.1073/pnas.0804871105
Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X (2009) Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 29:9090–9103. doi:10.1523/JNEUROSCI.1357-09.2009
Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K (2013) Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimers Dis 33(Suppl 1):S123–139. doi:10.3233/JAD-2012-129031
Xu J, Shi C, Li Q, Wu J, Forster EL, Yew DT (2007) Mitochondrial dysfunction in platelets and hippocampi of senescence-accelerated mice. J Bioenerg Biomembr 39:195–202. doi:10.1007/s10863-007-9077-y
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 USA 106:14670–14675. doi:10.1073/pnas.0903563106
Yin F, Boveris A, Cadenas E (2014) Mitochondrial energy metabolism and redox signaling in brain aging and neurodegeneration. Antioxid Redox Signal 20:353–371. doi:10.1089/ars.2012.4774
Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12:9–14. doi:10.1038/nrm3028
Zhu X, Perry G, Moreira PI, Aliev G, Cash AD, Hirai K, Smith MA (2006) Mitochondrial abnormalities and oxidative imbalance in Alzheimer disease. J Alzheimers Dis 9:147–153
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This work was supported by grants from Synapsis Foundation, Novartis Foundation for Biomedical Research Basel and the Swiss National Science Foundation (#31003A_149728) to AE.
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Grimm, A., Friedland, K. & Eckert, A. Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer’s disease. Biogerontology 17, 281–296 (2016). https://doi.org/10.1007/s10522-015-9618-4
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DOI: https://doi.org/10.1007/s10522-015-9618-4