Neurotoxicity Research

, Volume 22, Issue 3, pp 182–194 | Cite as

Alzheimer’s Disease Pathologic Cascades: Who Comes First, What Drives What

Review

Abstract

This review discusses known and speculated relationships between Alzheimer’s disease (AD) biochemical, molecular, and histologic phenomena. In the AD brain, various pathologies including neuritic plaques, neurofibrillary tangles, synaptic loss, oxidative stress, cell cycle re-entry, and mitochondrial changes have all been described. In an attempt to explain what exactly goes wrong in the AD brain various investigators have proposed different heuristic and hierarchical schemes. It is important to accurately define the AD pathology hierarchy because treatments targeting the true apex of its pathologic cascade arguably have the best chance of preventing, mitigating, or even curing this disease.

Keywords

Aging Alzheimer’s disease Amyloid Brain Oxidative stress Mitochondria 

Abbreviations

Beta amyloid

AD

Alzheimer’s disease

APP

Amyloid precursor protein

BACE

Beta secretase

COX

Cytochrome oxidase

ETC

Electron transport chain

FBD

Familial British dementia

FDD

Familial Danish dementia

GWAS

Genome wide association study

HCHWA

Hereditary cerebral hemorrhage with amyloidosis

mtDNA

Mitochondrial DNA

NOS

Nitric oxide synthase

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

References

  1. Adalbert R, Gilley J, Coleman MP (2007) Abeta, tau and ApoE4 in Alzheimer’s disease: the axonal connection. Trends Mol Med 13(4):135–142PubMedGoogle Scholar
  2. Alzheimer A (1907) Uber eine eigenartige Erkrankung der Hirnrinde. Allg Z Psychiat Psych-Gerichtl Med 64:146–148Google Scholar
  3. Alzheimer A (1911) Uber eigenartige Krankheitsfalle des spateren Alters. Z die Gesamte Neurologie Pscyhiatrie 4:456–485Google Scholar
  4. Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR (1995) An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin Anat 8(6):429–431PubMedGoogle Scholar
  5. Arendt T, Holzer M, Stobe A, Gartner U, Luth HJ, Bruckner MK, Ueberham U (2000) Activated mitogenic signaling induces a process of dedifferentiation in Alzheimer’s disease that eventually results in cell death. Ann N Y Acad Sci 920:249–255PubMedGoogle Scholar
  6. Arendt T, Stieler J, Strijkstra AM, Hut RA, Rudiger J, Van der Zee EA, Harkany T, Holzer M, Hartig W (2003) Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci 23(18):6972–6981PubMedGoogle Scholar
  7. Arriagada PV, Marzloff K, Hyman BT (1992) Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 42(9):1681–1688PubMedGoogle Scholar
  8. Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J, Hardy J, Lynch T, Bigio E, Hutton M (1999) Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 8(4):711–715PubMedGoogle Scholar
  9. Barrett MJ, Alones V, Wang KX, Phan L, Swerdlow RH (2004) Mitochondria-derived oxidative stress induces a heat shock protein response. J Neurosci Res 78(3):420–429PubMedGoogle Scholar
  10. Berg L, McKeel DW Jr, Miller JP, Baty J, Morris JC (1993) Neuropathological indexes of Alzheimer’s disease in demented and nondemented persons aged 80 years and older. Arch Neurol 50(4):349–358PubMedGoogle Scholar
  11. Berg L, McKeel DW Jr, Miller JP, Storandt M, Rubin EH, Morris JC, Baty J, Coats M, Norton J, Goate AM, Price JL, Gearing M, Mirra SS, Saunders AM (1998) Clinicopathologic studies in cognitively healthy aging and Alzheimer’s disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol 55(3):326–335PubMedGoogle Scholar
  12. Blass JP, Baker AC, Ko L, Black RS (1990) Induction of Alzheimer antigens by an uncoupler of oxidative phosphorylation. Arch Neurol 47(8):864–869PubMedGoogle Scholar
  13. Blocq P, Marinesco G (1892) Sur les lesions et la pathogenie de l’epilepsie dite essentielle. La Semaine Medicale 12:445–446Google Scholar
  14. Boveris A, Navarro A (2008) Brain mitochondrial dysfunction in aging. IUBMB Life 60(5):308–314PubMedGoogle Scholar
  15. Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16(3):271–278 discussion 278-284PubMedGoogle Scholar
  16. Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ, Miwa S, Pakay JL, Parker N (2004) Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med 37(6):755–767PubMedGoogle Scholar
  17. Brown GC (1999) Nitric oxide and mitochondrial respiration. Biochim Biophys Acta 1411(2–3):351–369PubMedGoogle Scholar
  18. Bruce-Keller AJ, White CL, Gupta S, Knight AG, Pistell PJ, Ingram DK, Morrison CD, Keller JN (2010) NOX activity in brain aging: exacerbation by high fat diet. Free Radic Biol Med 49(1):22–30PubMedGoogle Scholar
  19. Canevari L, Clark JB, Bates TE (1999) beta-Amyloid fragment 25–35 selectively decreases complex IV activity in isolated mitochondria. FEBS Lett 457(1):131–134PubMedGoogle Scholar
  20. Casley CS, Canevari L, Land JM, Clark JB, Sharpe MA (2002) Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J Neurochem 80(1):91–100PubMedGoogle Scholar
  21. Castellani RJ, Lee HG, Siedlak SL, Nunomura A, Hayashi T, Nakamura M, Zhu X, Perry G, Smith MA (2009) Reexamining Alzheimer’s disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta. J Alzheimers Dis 18(2):447–452PubMedGoogle Scholar
  22. Castellano JM, Kim J, Stewart FR, Jiang H, Demattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM (2011) Human apoE isoforms differentially regulate brain amyloid-{beta} peptide clearance. Sci Transl Med 3(89):89ra57PubMedGoogle Scholar
  23. Coleman PD, Yao PJ (2003) Synaptic slaughter in Alzheimer’s disease. Neurobiol Aging 24(8):1023–1027PubMedGoogle Scholar
  24. Corrada MM, Brookmeyer R, Paganini-Hill A, Berlau D, Kawas CH (2010) Dementia incidence continues to increase with age in the oldest old: the 90+ study. Ann Neurol 67(1):114–121PubMedGoogle Scholar
  25. Critchley M (1929) The nature and significance of senile plaques. J Neurol Psychopath 10:124–139Google Scholar
  26. Crouch PJ, Blake R, Duce JA, Ciccotosto GD, Li QX, Barnham KJ, Curtain CC, Cherny RA, Cappai R, Dyrks T, Masters CL, Trounce IA (2005) Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1–42. J Neurosci 25(3):672–679PubMedGoogle Scholar
  27. Curti D, Rognoni F, Gasparini L, Cattaneo A, Paolillo M, Racchi M, Zani L, Bianchetti A, Trabucchi M, Bergamaschi S, Govoni S (1997) Oxidative metabolism in cultured fibroblasts derived from sporadic Alzheimer’s disease (AD) patients. Neurosci Lett 236(1):13–16PubMedGoogle Scholar
  28. Davis JN II, Chisholm JC (1999) Alois Alzheimer and the amyloid debate. Nature 400(6747):810PubMedGoogle Scholar
  29. DeKosky ST, Scheff SW, Styren SD (1996) Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration 5(4):417–421PubMedGoogle Scholar
  30. Divry P (1927) Etude histochimique des plaques seniles. J Belg Neurol Psychiatry 9:643–657Google Scholar
  31. Dong H, Martin MV, Chambers S, Csernansky JG (2007) Spatial relationship between synapse loss and beta-amyloid deposition in Tg2576 mice. J Comp Neurol 500(2):311–321PubMedGoogle Scholar
  32. Dragicevic N, Mamcarz M, Zhu Y, Buzzeo R, Tan J, Arendash GW, Bradshaw PC (2010) 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 20(Suppl 2):S535–S550PubMedGoogle Scholar
  33. Du H, Guo L, Yan S, Sosunov AA, McKhann GM, Yan SS (2010) Early deficits in synaptic mitochondria in an Alzheimer’s disease mouse model. Proc Natl Acad Sci USA 107(43):18670–18675PubMedGoogle Scholar
  34. Elbaz A, Ross OA, Ioannidis JP, Soto-Ortolaza AI, Moisan F, Aasly J, Annesi G, Bozi M, Brighina L, Chartier-Harlin MC, Destee A, Ferrarese C, Ferraris A, Gibson JM, Gispert S, Hadjigeorgiou GM, Jasinska-Myga B, Klein C, Kruger R, Lambert JC, Lohmann K, van de Loo S, Loriot MA, Lynch T, Mellick GD, Mutez E, Nilsson C, Opala G, Puschmann A, Quattrone A, Sharma M, Silburn PA, Stefanis L, Uitti RJ, Valente EM, Vilarino-Guell C, Wirdefeldt K, Wszolek ZK, Xiromerisiou G, Maraganore DM, Farrer MJ (2011) Independent and joint effects of the MAPT and SNCA genes in Parkinson disease. Ann Neurol 69(5):778–792PubMedGoogle Scholar
  35. Finkel T (2001) Reactive oxygen species and signal transduction. IUBMB Life 52(1–2):3–6PubMedGoogle Scholar
  36. Finkel T (2003) Oxidant signals and oxidative stress. Curr Opin Cell Biol 15(2):247–254PubMedGoogle Scholar
  37. Fischer O (1907) Miliare Nekrosen mit drusigen Wucherungen der Neurofibrillen, eine regelmabige Veranderung der Hirnrinde bei seniler Demenz. Monatsschr Psychiatr Neurol 22:361–372Google Scholar
  38. Gabuzda D, Busciglio J, Chen LB, Matsudaira P, Yankner BA (1994) Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J Biol Chem 269(18):13623–13628PubMedGoogle Scholar
  39. Gasparini L, Racchi M, Benussi L, Curti D, Binetti G, Bianchetti A, Trabucchi M, Govoni S (1997) Effect of energy shortage and oxidative stress on amyloid precursor protein metabolism in COS cells. Neurosci Lett 231(2):113–117PubMedGoogle Scholar
  40. Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, Morrison JH, Gold G, Hof PR (2003) Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 60(9):1495–1500PubMedGoogle Scholar
  41. Glenner GG, Wong CW (1984a) Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 122(3):1131–1135PubMedGoogle Scholar
  42. Glenner GG, Wong CW (1984b) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120(3):885–890PubMedGoogle Scholar
  43. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349(6311):704–706PubMedGoogle Scholar
  44. Goedert M (1998) Neurofibrillary pathology of Alzheimer’s disease and other tauopathies. Prog Brain Res 117:287–306PubMedGoogle Scholar
  45. Goedert M, Klug A, Crowther RA (2006) Tau protein, the paired helical filament and Alzheimer’s disease. J Alzheimers Dis 9(3 Suppl):195–207PubMedGoogle Scholar
  46. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83(13):4913–4917PubMedGoogle Scholar
  47. Guyant-Marechal L, Rovelet-Lecrux A, Goumidi L, Cousin E, Hannequin D, Raux G, Penet C, Ricard S, Mace S, Amouyel P, Deleuze JF, Frebourg T, Brice A, Lambert JC, Campion D (2007) Variations in the APP gene promoter region and risk of Alzheimer disease. Neurology 68(9):684–687PubMedGoogle Scholar
  48. Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12(10):383–388PubMedGoogle Scholar
  49. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185PubMedGoogle Scholar
  50. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356PubMedGoogle Scholar
  51. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O’Donovan M, Owen MJ, Williams J (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41(10):1088–1093PubMedGoogle Scholar
  52. Hartig W, Stieler J, Boerema AS, Wolf J, Schmidt U, Weissfuss J, Bullmann T, Strijkstra AM, Arendt T (2007) Hibernation model of tau phosphorylation in hamsters: selective vulnerability of cholinergic basal forebrain neurons—implications for Alzheimer’s disease. Eur J Neurosci 25(1):69–80PubMedGoogle Scholar
  53. 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 30(10):1574–1586PubMedGoogle Scholar
  54. Herrup K (2010) Reimagining Alzheimer’s disease—an age-based hypothesis. J Neurosci 30(50):16755–16762PubMedGoogle Scholar
  55. Herrup K, Arendt T (2002) Re-expression of cell cycle proteins induces neuronal cell death during Alzheimer’s disease. J Alzheimers Dis 4(3):243–247PubMedGoogle Scholar
  56. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21(9):3017–3023PubMedGoogle Scholar
  57. Hof PR, Glannakopoulos P, Bouras C (1996) The neuropathological changes associated with normal brain aging. Histol Histopathol 11(4):1075–1088PubMedGoogle Scholar
  58. Holton JL, Ghiso J, Lashley T, Rostagno A, Guerin CJ, Gibb G, Houlden H, Ayling H, Martinian L, Anderton BH, Wood NW, Vidal R, Plant G, Frangione B, Revesz T (2001) Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia. Am J Pathol 158(2):515–526PubMedGoogle Scholar
  59. Holton JL, Lashley T, Ghiso J, Braendgaard H, Vidal R, Guerin CJ, Gibb G, Hanger DP, Rostagno A, Anderton BH, Strand C, Ayling H, Plant G, Frangione B, Bojsen-Moller M, Revesz T (2002) Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta. J Neuropathol Exp Neurol 61(3):254–267PubMedGoogle Scholar
  60. Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9(1):119–128PubMedGoogle Scholar
  61. Jun G, Naj AC, Beecham GW, Wang LS, Buros J, Gallins PJ, Buxbaum JD, Ertekin-Taner N, Fallin MD, Friedland R, Inzelberg R, Kramer P, Rogaeva E, St George-Hyslop P, Cantwell LB, Dombroski BA, Saykin AJ, Reiman EM, Bennett DA, Morris JC, Lunetta KL, Martin ER, Montine TJ, Goate AM, Blacker D, Tsuang DW, Beekly D, Cupples LA, Hakonarson H, Kukull W, Foroud TM, Haines J, Mayeux R, Farrer LA, Pericak-Vance MA, Schellenberg GD (2010) Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 67(12):1473–1484PubMedGoogle Scholar
  62. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325(6106):733–736PubMedGoogle Scholar
  63. Khan SM, Cassarino DS, Abramova NN, Keeney PM, Borland MK, Trimmer PA, Krebs CT, Bennett JC, Parks JK, Swerdlow RH, Parker WD Jr, Bennett JP Jr (2000) Alzheimer’s disease cybrids replicate beta-amyloid abnormalities through cell death pathways. Ann Neurol 48(2):148–155PubMedGoogle Scholar
  64. Kraepelin E (1910) Psychiatrie. Ein Lehrbuch fur Studierende und Arzte. Klinishce Psychiatrie Verlag Johann Ambrosius Barth, LepzigGoogle Scholar
  65. Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309(5733):481–484PubMedGoogle Scholar
  66. Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159PubMedGoogle Scholar
  67. Lee HG, Zhu X, Nunomura A, Perry G, Smith MA (2006) Amyloid beta: the alternate hypothesis. Curr Alzheimer Res 3(1):75–80PubMedGoogle Scholar
  68. Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GT, Luyendijk W, Frangione B (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248(4959):1124–1126PubMedGoogle Scholar
  69. Lin MT, Simon DK, Ahn CH, Kim LM, Beal MF (2002) High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer’s disease brain. Hum Mol Genet 11(2):133–145PubMedGoogle Scholar
  70. Lovestone S, Reynolds CH (1997) The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes. Neuroscience 78(2):309–324PubMedGoogle Scholar
  71. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82(12):4245–4249PubMedGoogle Scholar
  72. McShea A, Harris PL, Webster KR, Wahl AF, Smith MA (1997) Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer’s disease. Am J Pathol 150(6):1933–1939PubMedGoogle Scholar
  73. McShea A, Lee HG, Petersen RB, Casadesus G, Vincent I, Linford NJ, Funk JO, Shapiro RA, Smith MA (2007) Neuronal cell cycle re-entry mediates Alzheimer disease-type changes. Biochim Biophys Acta 1772(4):467–472PubMedGoogle Scholar
  74. Mead S, James-Galton M, Revesz T, Doshi RB, Harwood G, Pan EL, Ghiso J, Frangione B, Plant G (2000) Familial British dementia with amyloid angiopathy: early clinical, neuropsychological and imaging findings. Brain 123(Pt 5):975–991PubMedGoogle Scholar
  75. Minnick DT, Pavlov YI, Kunkel TA (1994) The fidelity of the human leading and lagging strand DNA replication apparatus with 8-oxodeoxyguanosine triphosphate. Nucleic Acids Res 22(25):5658–5664PubMedGoogle Scholar
  76. Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G (2010a) Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochim Biophys Acta 1802(1):2–10PubMedGoogle Scholar
  77. Moreira PI, Zhu X, Wang X, Lee HG, Nunomura A, Petersen RB, Perry G, Smith MA (2010b) Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta 1802(1):212–220PubMedGoogle Scholar
  78. Mosch B, Morawski M, Mittag A, Lenz D, Tarnok A, Arendt T (2007) Aneuploidy and DNA replication in the normal human brain and Alzheimer’s disease. J Neurosci 27(26):6859–6867PubMedGoogle Scholar
  79. Mukherjee O, Kauwe JS, Mayo K, Morris JC, Goate AM (2007) Haplotype-based association analysis of the MAPT locus in late onset Alzheimer’s disease. BMC Genet 8:3PubMedGoogle Scholar
  80. Myers AJ, Kaleem M, Marlowe L, Pittman AM, Lees AJ, Fung HC, Duckworth J, Leung D, Gibson A, Morris CM, de Silva R, Hardy J (2005) The H1c haplotype at the MAPT locus is associated with Alzheimer’s disease. Hum Mol Genet 14(16):2399–2404PubMedGoogle Scholar
  81. Nagy Z, Jobst KA, Esiri MM, Morris JH, King EM, MacDonald B, Litchfield S, Barnetson L, Smith AD (1996) Hippocampal pathology reflects memory deficit and brain imaging measurements in Alzheimer’s disease: clinicopathologic correlations using three sets of pathologic diagnostic criteria. Dementia 7(2):76–81PubMedGoogle Scholar
  82. Nagy Z, Esiri MM, Smith AD (1998) The cell division cycle and the pathophysiology of Alzheimer’s disease. Neuroscience 87(4):731–739PubMedGoogle Scholar
  83. Navarro A, Boveris A (2007) The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 292(2):C670–C686PubMedGoogle Scholar
  84. Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, Smith MA (1999) RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J Neurosci 19(6):1959–1964PubMedGoogle Scholar
  85. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60(8):759–767PubMedGoogle Scholar
  86. Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM (2004) Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43(3):321–332PubMedGoogle Scholar
  87. Ozawa T (1997) Genetic and functional changes in mitochondria associated with aging. Physiol Rev 77(2):425–464PubMedGoogle Scholar
  88. Parker WD Jr, Filley CM, Parks JK (1990) Cytochrome oxidase deficiency in Alzheimer’s disease. Neurology 40(8):1302–1303PubMedGoogle Scholar
  89. Pavlov YI, Minnick DT, Izuta S, Kunkel TA (1994) DNA replication fidelity with 8-oxodeoxyguanosine triphosphate. Biochemistry 33(15):4695–4701PubMedGoogle Scholar
  90. Pereira C, Santos MS, Oliveira C (1998) Mitochondrial function impairment induced by amyloid beta-peptide on PC12 cells. Neuroreport 9(8):1749–1755PubMedGoogle Scholar
  91. Perry G, Nunomura A, Raina AK, Smith MA (2000) Amyloid-beta junkies. Lancet 355(9205):757PubMedGoogle Scholar
  92. Perry G, Nunomura A, Hirai K, Zhu X, Perez M, Avila J, Castellani RJ, Atwood CS, Aliev G, Sayre LM, Takeda A, Smith MA (2002) Is oxidative damage the fundamental pathogenic mechanism of Alzheimer’s and other neurodegenerative diseases? Free Radic Biol Med 33(11):1475–1479PubMedGoogle Scholar
  93. Petersen RB, Nunomura A, Lee HG, Casadesus G, Perry G, Smith MA, Zhu X (2007) Signal transduction cascades associated with oxidative stress in Alzheimer’s disease. J Alzheimers Dis 11(2):143–152PubMedGoogle Scholar
  94. Pittman AM, Fung HC, de Silva R (2006) Untangling the tau gene association with neurodegenerative disorders. Hum Mol Genet 15 Spec No 2:R188–R195PubMedGoogle Scholar
  95. Redlich E (1898) Über miliare Sklerosen der Hirnrinde bei seniler Atrophie. Jahrb Psychiat Neurol 17:208–216Google Scholar
  96. Revesz T, Holton JL, Lashley T, Plant G, Frangione B, Rostagno A, Ghiso J (2009) Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies. Acta Neuropathol 118(1):115–130PubMedGoogle Scholar
  97. Riobo NA, Clementi E, Melani M, Boveris A, Cadenas E, Moncada S, Poderoso JJ (2001) Nitric oxide inhibits mitochondrial NADH: ubiquinone reductase activity through peroxynitrite formation. Biochem J 359(Pt 1):139–145PubMedGoogle Scholar
  98. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39(2):168–177PubMedGoogle Scholar
  99. Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten JC (2011) Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry 82(5):476–486PubMedGoogle Scholar
  100. Sergeant N, Wattez A, Delacourte A (1999) Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusively “exon 10” isoforms. J Neurochem 72(3):1243–1249PubMedGoogle Scholar
  101. Shigenaga MK, Hagen TM, Ames BN (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91(23):10771–10778PubMedGoogle Scholar
  102. Singh D, Greenwald JE, Bianchine J, Metz EN, Sagone AL Jr (1981) Evidence for the generation of hydroxyl radical during arachidonic acid metabolism by human platelets. Am J Hematol 11(3):233–240PubMedGoogle Scholar
  103. Sipe JD, Cohen AS (2000) Review: history of the amyloid fibril. J Struct Biol 130(2–3):88–98PubMedGoogle Scholar
  104. Smith MA, Kutty RK, Richey PL, Yan SD, Stern D, Chader GJ, Wiggert B, Petersen RB, Perry G (1994) Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer’s disease. Am J Pathol 145(1):42–47PubMedGoogle Scholar
  105. Smith MA, Rudnicka-Nawrot M, Richey PL, Praprotnik D, Mulvihill P, Miller CA, Sayre LM, Perry G (1995) Carbonyl-related posttranslational modification of neurofilament protein in the neurofibrillary pathology of Alzheimer’s disease. J Neurochem 64(6):2660–2666PubMedGoogle Scholar
  106. Smith MA, Drew KL, Nunomura A, Takeda A, Hirai K, Zhu X, Atwood CS, Raina AK, Rottkamp CA, Sayre LM, Friedland RP, Perry G (2002) Amyloid-beta, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs? Neurochem Int 40(6):527–531PubMedGoogle Scholar
  107. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3):280–292PubMedGoogle Scholar
  108. Swerdlow RH (2007a) Is aging part of Alzheimer’s disease, or is Alzheimer’s disease part of aging? Neurobiol Aging 28(10):1465–1480PubMedGoogle Scholar
  109. Swerdlow RH (2007b) Mitochondria in cybrids containing mtDNA from persons with mitochondriopathies. J Neurosci Res 85(15):3416–3428PubMedGoogle Scholar
  110. Swerdlow RH (2007c) Pathogenesis of Alzheimer’s disease. Clin Interv Aging 2(3):347–359PubMedGoogle Scholar
  111. Swerdlow RH (2007d) Treating neurodegeneration by modifying mitochondria: potential solutions to a “complex” problem. Antioxid Redox Signal 9(10):1591–1603PubMedGoogle Scholar
  112. Swerdlow RH (2009) The neurodegenerative mitochondriopathies. J Alzheimers Dis 17(4):737–751PubMedGoogle Scholar
  113. Swerdlow RH (2011) Mitochondria and cell bioenergetics: increasingly recognized components and a possible etiologic cause of Alzheimer’s disease. Antioxid Redox Signal (in press)Google Scholar
  114. Swerdlow RH, Khan SM (2004) A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med Hypotheses 63(1):8–20PubMedGoogle Scholar
  115. Swerdlow RH, Khan SM (2009) The Alzheimer’s disease mitochondrial cascade hypothesis: an update. Exp Neurol 218(2):308–315PubMedGoogle Scholar
  116. Swerdlow RH, Kish SJ (2002) Mitochondria in Alzheimer’s disease. Int Rev Neurobiol 53:341–385PubMedGoogle Scholar
  117. Swerdlow RH, Parks JK, Cassarino DS, Maguire DJ, Maguire RS, Bennett JP Jr, Davis RE, Parker WD Jr (1997) Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology 49(4):918–925PubMedGoogle Scholar
  118. Swerdlow RH, Burns JM, Khan SM (2010) The Alzheimer’s disease mitochondrial cascade hypothesis. J Alzheimers Dis 20(Suppl 2):S265–S279PubMedGoogle Scholar
  119. Szabados T, Dul C, Majtenyi K, Hargitai J, Penzes Z, Urbanics R (2004) A chronic Alzheimer’s model evoked by mitochondrial poison sodium azide for pharmacological investigations. Behav Brain Res 154(1):31–40PubMedGoogle Scholar
  120. Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, Pronzato MA, Danni O, Smith MA, Perry G, Tabaton M (2002) Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis 10(3):279–288PubMedGoogle Scholar
  121. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30(4):572–580PubMedGoogle Scholar
  122. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, Larsson NG (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429(6990):417–423PubMedGoogle Scholar
  123. Varadarajan S, Yatin S, Kanski J, Jahanshahi F, Butterfield DA (1999) Methionine residue 35 is important in amyloid beta-peptide-associated free radical oxidative stress. Brain Res Bull 50(2):133–141PubMedGoogle Scholar
  124. Vincent I, Rosado M, Davies P (1996) Mitotic mechanisms in Alzheimer’s disease? J Cell Biol 132(3):413–425PubMedGoogle Scholar
  125. Vincent I, Zheng JH, Dickson DW, Kress Y, Davies P (1998) Mitotic phosphoepitopes precede paired helical filaments in Alzheimer’s disease. Neurobiol Aging 19(4):287–296PubMedGoogle Scholar
  126. Walsh DM, Selkoe DJ (2007) A beta oligomers—a decade of discovery. J Neurochem 101(5):1172–1184PubMedGoogle Scholar
  127. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416(6880):535–539PubMedGoogle Scholar
  128. Webster MT, Pearce BR, Bowen DM, Francis PT (1998) The effects of perturbed energy metabolism on the processing of amyloid precursor protein in PC12 cells. J Neural Transm 105(8–9):839–853PubMedGoogle Scholar
  129. Yanagisawa M, Planel E, Ishiguro K, Fujita SC (1999) Starvation induces tau hyperphosphorylation in mouse brain: implications for Alzheimer’s disease. FEBS Lett 461(3):329–333PubMedGoogle Scholar
  130. Yang Y, Geldmacher DS, Herrup K (2001) DNA replication precedes neuronal cell death in Alzheimer’s disease. J Neurosci 21(8):2661–2668PubMedGoogle Scholar
  131. Yang Y, Mufson EJ, Herrup K (2003) Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer’s disease. J Neurosci 23(7):2557–2563PubMedGoogle Scholar
  132. Yang Y, Varvel NH, Lamb BT, Herrup K (2006) Ectopic cell cycle events link human Alzheimer’s disease and amyloid precursor protein transgenic mouse models. J Neurosci 26(3):775–784PubMedGoogle Scholar
  133. Yankner BA, Dawes LR, Fisher S, Villa-Komaroff L, Oster-Granite ML, Neve RL (1989) Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease. Science 245(4916):417–420PubMedGoogle Scholar
  134. Zhu X, Castellani RJ, Takeda A, Nunomura A, Atwood CS, Perry G, Smith MA (2001) Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the ‘two hit’ hypothesis. Mech Ageing Dev 123(1):39–46PubMedGoogle Scholar
  135. Zhu X, McShea A, Harris PL, Raina AK, Castellani RJ, Funk JO, Shah S, Atwood C, Bowen R, Bowser R, Morelli L, Perry G, Smith MA (2004a) Elevated expression of a regulator of the G2/M phase of the cell cycle, neuronal CIP-1-associated regulator of cyclin B, in Alzheimer’s disease. J Neurosci Res 75(5):698–703PubMedGoogle Scholar
  136. Zhu X, Raina AK, Perry G, Smith MA (2004b) Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol 3(4):219–226PubMedGoogle Scholar
  137. Zhu X, Lee HG, Perry G, Smith MA (2007) Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta 1772(4):494–502PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of Kansas Medical CenterKansas CityUSA
  2. 2.Department of Biochemistry and Molecular BiologyUniversity of Kansas Medical CenterKansas CityUSA
  3. 3.Department of Molecular and Integrative PhysiologyUniversity of Kansas Medical CenterKansas CityUSA
  4. 4.University of Kansas School of MedicineKansas CityUSA

Personalised recommendations