Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

Aβ:

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

  • Adalbert R, Gilley J, Coleman MP (2007) Abeta, tau and ApoE4 in Alzheimer’s disease: the axonal connection. Trends Mol Med 13(4):135–142

    PubMed  CAS  Google Scholar 

  • Alzheimer A (1907) Uber eine eigenartige Erkrankung der Hirnrinde. Allg Z Psychiat Psych-Gerichtl Med 64:146–148

    Google Scholar 

  • Alzheimer A (1911) Uber eigenartige Krankheitsfalle des spateren Alters. Z die Gesamte Neurologie Pscyhiatrie 4:456–485

    Google Scholar 

  • 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):429–431

    PubMed  CAS  Google Scholar 

  • 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 920:249–255

    PubMed  CAS  Google Scholar 

  • 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):6972–6981

    PubMed  CAS  Google Scholar 

  • 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):1681–1688

    PubMed  CAS  Google Scholar 

  • 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):711–715

    PubMed  CAS  Google Scholar 

  • 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):420–429

    PubMed  CAS  Google Scholar 

  • 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):349–358

    PubMed  CAS  Google Scholar 

  • 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):326–335

    PubMed  CAS  Google Scholar 

  • Blass JP, Baker AC, Ko L, Black RS (1990) Induction of Alzheimer antigens by an uncoupler of oxidative phosphorylation. Arch Neurol 47(8):864–869

    PubMed  CAS  Google Scholar 

  • Blocq P, Marinesco G (1892) Sur les lesions et la pathogenie de l’epilepsie dite essentielle. La Semaine Medicale 12:445–446

    Google Scholar 

  • Boveris A, Navarro A (2008) Brain mitochondrial dysfunction in aging. IUBMB Life 60(5):308–314

    PubMed  CAS  Google Scholar 

  • Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16(3):271–278 discussion 278-284

    PubMed  CAS  Google Scholar 

  • 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):755–767

    PubMed  CAS  Google Scholar 

  • Brown GC (1999) Nitric oxide and mitochondrial respiration. Biochim Biophys Acta 1411(2–3):351–369

    PubMed  CAS  Google Scholar 

  • 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):22–30

    PubMed  CAS  Google Scholar 

  • Canevari L, Clark JB, Bates TE (1999) beta-Amyloid fragment 25–35 selectively decreases complex IV activity in isolated mitochondria. FEBS Lett 457(1):131–134

    PubMed  CAS  Google Scholar 

  • 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):91–100

    PubMed  CAS  Google Scholar 

  • 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):447–452

    PubMed  CAS  Google Scholar 

  • 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):89ra57

    PubMed  CAS  Google Scholar 

  • Coleman PD, Yao PJ (2003) Synaptic slaughter in Alzheimer’s disease. Neurobiol Aging 24(8):1023–1027

    PubMed  CAS  Google Scholar 

  • 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):114–121

    PubMed  Google Scholar 

  • Critchley M (1929) The nature and significance of senile plaques. J Neurol Psychopath 10:124–139

    CAS  Google Scholar 

  • 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):672–679

    PubMed  CAS  Google Scholar 

  • 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):13–16

    PubMed  CAS  Google Scholar 

  • Davis JN II, Chisholm JC (1999) Alois Alzheimer and the amyloid debate. Nature 400(6747):810

    PubMed  Google Scholar 

  • DeKosky ST, Scheff SW, Styren SD (1996) Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration 5(4):417–421

    PubMed  CAS  Google Scholar 

  • Divry P (1927) Etude histochimique des plaques seniles. J Belg Neurol Psychiatry 9:643–657

    Google Scholar 

  • 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):311–321

    PubMed  CAS  Google Scholar 

  • 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–S550

    PubMed  Google Scholar 

  • 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):18670–18675

    PubMed  CAS  Google Scholar 

  • 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):778–792

    PubMed  CAS  Google Scholar 

  • Finkel T (2001) Reactive oxygen species and signal transduction. IUBMB Life 52(1–2):3–6

    PubMed  CAS  Google Scholar 

  • Finkel T (2003) Oxidant signals and oxidative stress. Curr Opin Cell Biol 15(2):247–254

    PubMed  CAS  Google Scholar 

  • Fischer O (1907) Miliare Nekrosen mit drusigen Wucherungen der Neurofibrillen, eine regelmabige Veranderung der Hirnrinde bei seniler Demenz. Monatsschr Psychiatr Neurol 22:361–372

    Google Scholar 

  • 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):13623–13628

    PubMed  CAS  Google Scholar 

  • 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):113–117

    PubMed  CAS  Google Scholar 

  • 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):1495–1500

    PubMed  CAS  Google Scholar 

  • 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):1131–1135

    PubMed  CAS  Google Scholar 

  • 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):885–890

    PubMed  CAS  Google Scholar 

  • 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):704–706

    PubMed  CAS  Google Scholar 

  • Goedert M (1998) Neurofibrillary pathology of Alzheimer’s disease and other tauopathies. Prog Brain Res 117:287–306

    PubMed  CAS  Google Scholar 

  • Goedert M, Klug A, Crowther RA (2006) Tau protein, the paired helical filament and Alzheimer’s disease. J Alzheimers Dis 9(3 Suppl):195–207

    PubMed  CAS  Google Scholar 

  • 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):4913–4917

    PubMed  CAS  Google Scholar 

  • 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):684–687

    PubMed  CAS  Google Scholar 

  • Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12(10):383–388

    PubMed  CAS  Google Scholar 

  • Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185

    PubMed  CAS  Google Scholar 

  • Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356

    PubMed  CAS  Google Scholar 

  • 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):1088–1093

    PubMed  CAS  Google Scholar 

  • 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):69–80

    PubMed  Google Scholar 

  • 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):1574–1586

    PubMed  CAS  Google Scholar 

  • Herrup K (2010) Reimagining Alzheimer’s disease—an age-based hypothesis. J Neurosci 30(50):16755–16762

    PubMed  CAS  Google Scholar 

  • Herrup K, Arendt T (2002) Re-expression of cell cycle proteins induces neuronal cell death during Alzheimer’s disease. J Alzheimers Dis 4(3):243–247

    PubMed  CAS  Google Scholar 

  • 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):3017–3023

    PubMed  CAS  Google Scholar 

  • Hof PR, Glannakopoulos P, Bouras C (1996) The neuropathological changes associated with normal brain aging. Histol Histopathol 11(4):1075–1088

    PubMed  CAS  Google Scholar 

  • 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):515–526

    PubMed  CAS  Google Scholar 

  • 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):254–267

    PubMed  CAS  Google Scholar 

  • 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):119–128

    PubMed  CAS  Google Scholar 

  • 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):1473–1484

    PubMed  Google Scholar 

  • 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):733–736

    PubMed  CAS  Google Scholar 

  • 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):148–155

    PubMed  CAS  Google Scholar 

  • Kraepelin E (1910) Psychiatrie. Ein Lehrbuch fur Studierende und Arzte. Klinishce Psychiatrie Verlag Johann Ambrosius Barth, Lepzig

    Google Scholar 

  • 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):481–484

    PubMed  CAS  Google Scholar 

  • Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159

    PubMed  CAS  Google Scholar 

  • Lee HG, Zhu X, Nunomura A, Perry G, Smith MA (2006) Amyloid beta: the alternate hypothesis. Curr Alzheimer Res 3(1):75–80

    PubMed  CAS  Google Scholar 

  • 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):1124–1126

    PubMed  CAS  Google Scholar 

  • 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):133–145

    PubMed  CAS  Google Scholar 

  • Lovestone S, Reynolds CH (1997) The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes. Neuroscience 78(2):309–324

    PubMed  CAS  Google Scholar 

  • 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):4245–4249

    PubMed  CAS  Google Scholar 

  • 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):1933–1939

    PubMed  CAS  Google Scholar 

  • 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):467–472

    PubMed  CAS  Google Scholar 

  • 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):975–991

    PubMed  Google Scholar 

  • 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):5658–5664

    PubMed  CAS  Google Scholar 

  • 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):2–10

    PubMed  CAS  Google Scholar 

  • 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):212–220

    PubMed  CAS  Google Scholar 

  • 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):6859–6867

    PubMed  CAS  Google Scholar 

  • 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 8:3

    PubMed  Google Scholar 

  • 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):2399–2404

    PubMed  CAS  Google Scholar 

  • 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):76–81

    PubMed  CAS  Google Scholar 

  • Nagy Z, Esiri MM, Smith AD (1998) The cell division cycle and the pathophysiology of Alzheimer’s disease. Neuroscience 87(4):731–739

    PubMed  CAS  Google Scholar 

  • Navarro A, Boveris A (2007) The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 292(2):C670–C686

    PubMed  CAS  Google Scholar 

  • 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):1959–1964

    PubMed  CAS  Google Scholar 

  • 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):759–767

    PubMed  CAS  Google Scholar 

  • 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):321–332

    PubMed  CAS  Google Scholar 

  • Ozawa T (1997) Genetic and functional changes in mitochondria associated with aging. Physiol Rev 77(2):425–464

    PubMed  CAS  Google Scholar 

  • Parker WD Jr, Filley CM, Parks JK (1990) Cytochrome oxidase deficiency in Alzheimer’s disease. Neurology 40(8):1302–1303

    PubMed  Google Scholar 

  • Pavlov YI, Minnick DT, Izuta S, Kunkel TA (1994) DNA replication fidelity with 8-oxodeoxyguanosine triphosphate. Biochemistry 33(15):4695–4701

    PubMed  CAS  Google Scholar 

  • Pereira C, Santos MS, Oliveira C (1998) Mitochondrial function impairment induced by amyloid beta-peptide on PC12 cells. Neuroreport 9(8):1749–1755

    PubMed  CAS  Google Scholar 

  • Perry G, Nunomura A, Raina AK, Smith MA (2000) Amyloid-beta junkies. Lancet 355(9205):757

    PubMed  CAS  Google Scholar 

  • 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):1475–1479

    PubMed  CAS  Google Scholar 

  • 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):143–152

    PubMed  CAS  Google Scholar 

  • Pittman AM, Fung HC, de Silva R (2006) Untangling the tau gene association with neurodegenerative disorders. Hum Mol Genet 15 Spec No 2:R188–R195

    PubMed  Google Scholar 

  • Redlich E (1898) Über miliare Sklerosen der Hirnrinde bei seniler Atrophie. Jahrb Psychiat Neurol 17:208–216

    Google Scholar 

  • 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):115–130

    PubMed  CAS  Google Scholar 

  • 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):139–145

    PubMed  CAS  Google Scholar 

  • 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):168–177

    PubMed  CAS  Google Scholar 

  • 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):476–486

    PubMed  Google Scholar 

  • 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):1243–1249

    PubMed  CAS  Google Scholar 

  • Shigenaga MK, Hagen TM, Ames BN (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91(23):10771–10778

    PubMed  CAS  Google Scholar 

  • 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):233–240

    PubMed  CAS  Google Scholar 

  • Sipe JD, Cohen AS (2000) Review: history of the amyloid fibril. J Struct Biol 130(2–3):88–98

    PubMed  CAS  Google Scholar 

  • 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):42–47

    PubMed  CAS  Google Scholar 

  • 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):2660–2666

    PubMed  CAS  Google Scholar 

  • 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):527–531

    PubMed  CAS  Google Scholar 

  • 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):280–292

    PubMed  Google Scholar 

  • Swerdlow RH (2007a) Is aging part of Alzheimer’s disease, or is Alzheimer’s disease part of aging? Neurobiol Aging 28(10):1465–1480

    PubMed  Google Scholar 

  • Swerdlow RH (2007b) Mitochondria in cybrids containing mtDNA from persons with mitochondriopathies. J Neurosci Res 85(15):3416–3428

    PubMed  CAS  Google Scholar 

  • Swerdlow RH (2007c) Pathogenesis of Alzheimer’s disease. Clin Interv Aging 2(3):347–359

    PubMed  CAS  Google Scholar 

  • Swerdlow RH (2007d) Treating neurodegeneration by modifying mitochondria: potential solutions to a “complex” problem. Antioxid Redox Signal 9(10):1591–1603

    PubMed  CAS  Google Scholar 

  • Swerdlow RH (2009) The neurodegenerative mitochondriopathies. J Alzheimers Dis 17(4):737–751

    PubMed  CAS  Google Scholar 

  • Swerdlow RH (2011) Mitochondria and cell bioenergetics: increasingly recognized components and a possible etiologic cause of Alzheimer’s disease. Antioxid Redox Signal (in press)

  • Swerdlow RH, Khan SM (2004) A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med Hypotheses 63(1):8–20

    PubMed  CAS  Google Scholar 

  • Swerdlow RH, Khan SM (2009) The Alzheimer’s disease mitochondrial cascade hypothesis: an update. Exp Neurol 218(2):308–315

    PubMed  CAS  Google Scholar 

  • Swerdlow RH, Kish SJ (2002) Mitochondria in Alzheimer’s disease. Int Rev Neurobiol 53:341–385

    PubMed  CAS  Google Scholar 

  • 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):918–925

    PubMed  CAS  Google Scholar 

  • Swerdlow RH, Burns JM, Khan SM (2010) The Alzheimer’s disease mitochondrial cascade hypothesis. J Alzheimers Dis 20(Suppl 2):S265–S279

    PubMed  Google Scholar 

  • 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):31–40

    PubMed  CAS  Google Scholar 

  • 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):279–288

    PubMed  CAS  Google Scholar 

  • 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):572–580

    PubMed  CAS  Google Scholar 

  • 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):417–423

    PubMed  CAS  Google Scholar 

  • 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):133–141

    PubMed  CAS  Google Scholar 

  • Vincent I, Rosado M, Davies P (1996) Mitotic mechanisms in Alzheimer’s disease? J Cell Biol 132(3):413–425

    PubMed  CAS  Google Scholar 

  • 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):287–296

    PubMed  CAS  Google Scholar 

  • Walsh DM, Selkoe DJ (2007) A beta oligomers—a decade of discovery. J Neurochem 101(5):1172–1184

    PubMed  CAS  Google Scholar 

  • 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):535–539

    PubMed  CAS  Google Scholar 

  • 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):839–853

    PubMed  CAS  Google Scholar 

  • 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):329–333

    PubMed  CAS  Google Scholar 

  • Yang Y, Geldmacher DS, Herrup K (2001) DNA replication precedes neuronal cell death in Alzheimer’s disease. J Neurosci 21(8):2661–2668

    PubMed  CAS  Google Scholar 

  • 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):2557–2563

    PubMed  CAS  Google Scholar 

  • 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):775–784

    PubMed  CAS  Google Scholar 

  • 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):417–420

    PubMed  CAS  Google Scholar 

  • 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):39–46

    PubMed  CAS  Google Scholar 

  • 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):698–703

    PubMed  CAS  Google Scholar 

  • Zhu X, Raina AK, Perry G, Smith MA (2004b) Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol 3(4):219–226

    PubMed  CAS  Google Scholar 

  • Zhu X, Lee HG, Perry G, Smith MA (2007) Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta 1772(4):494–502

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The author is supported by P30AG035982 and the Morgan Family Foundation.

Author information

Authors and Affiliations

  1. Department of Neurology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Russell H. Swerdlow

  2. Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Russell H. Swerdlow

  3. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Russell H. Swerdlow

  4. University of Kansas School of Medicine, MS 2012, Landon Center on Aging, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA

    Russell H. Swerdlow

Authors
  1. Russell H. Swerdlow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Russell H. Swerdlow.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Swerdlow, R.H. Alzheimer’s Disease Pathologic Cascades: Who Comes First, What Drives What. Neurotox Res 22, 182–194 (2012). https://doi.org/10.1007/s12640-011-9272-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-011-9272-9

Keywords

Search

Navigation