Brain Structure and Function

, Volume 214, Issue 2–3, pp 201–218 | Cite as

Immunotherapeutic approaches for Alzheimer’s disease in transgenic mouse models

Review

Abstract

Alzheimer’s disease (AD) is a member of a category of neurodegenerative diseases characterized by the conformational change of a normal protein into a pathological conformer with a high β-sheet content that renders it resistant to degradation and neurotoxic. In the case of AD the normal soluble amyloid β (sAβ) peptide is converted into oligomeric/fibrillar Aβ. The oligomeric forms of Aβ are thought to be the most toxic, while fibrillar Aβ becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is an essential part of the pathology. Many therapeutic interventions are under investigation to prevent and treat AD. The testing of these diverse approaches to ameliorate AD pathology has been made possible by the existence of numerous transgenic mouse models which each mirror different aspects of AD pathology. Perhaps the most exciting of these approaches is immunomodulation. Vaccination is currently being tried for a range of age associated CNS disorders with great success being reported in many transgenic mouse models. However, there is a discrepancy between these results and current human clinical trials which highlights the limitations of current models and also uncertainties in our understanding of the underlying pathogenesis of AD. No current AD Tg mouse model exactly reflects all aspects of the human disease. Since the underlying etiology of sporadic AD is unknown, the process of creating better Tg models is in constant evolution. This is an essential goal since it will be necessary to develop therapeutic approaches which will be highly effective in humans.

Keywords

Transgenic mice Amyloid β Congophilic angiopathy Tau Vaccination Immunomodulation Alzheimer’s disease 

Notes

Acknowledgments

This manuscript was supported by NIH grants AG20245 and AG15408.

References

  1. Agadjanyan MG, Ghochikyan A, Petrushina I, Vasilevko V, Movsesyan N, Mkrtichyan M, Saing T, Cribbs DH (2005) Prototype Alzheimer’s disease vaccine using the immunodominant B cell epitope from beta-amyloid and promiscuous T cell epitope pan HLA DR-binding peptide. J Immunol 174:1580–1586PubMedGoogle Scholar
  2. Aguzzi A (2009) Cell biology: beyond the prion principle. Nature 459:924–925PubMedGoogle Scholar
  3. Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582–590Google Scholar
  4. Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P (2005) Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 25:5446–5454PubMedGoogle Scholar
  5. Arendash GW, King DL, Gordon MN, Morgan D, Hatcher JM, Hope CE, Diamond DM (2001) Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes. Brain Res 891:42–53PubMedGoogle Scholar
  6. Asuni A, Boutajangout A, Scholtzova H, Knudsen E, Li Y, Quartermain D, Frangione B, Wisniewski T, Sigurdsson EM (2006) Aβ derivative vaccination in alum adjuvant prevents amyloid deposition and does not cause brain microhemorrhages in Alzheimer’s model mice. Eur J Neurosci 24:2530–2542PubMedGoogle Scholar
  7. Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM (2007) Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci 27:9115–9129PubMedGoogle Scholar
  8. Attems J, Jellinger KA (2004) Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology—a pilot study. Acta Neuropathol (Berl) 107:83–90Google Scholar
  9. Bales KR, Verina T, Dodel RC, Du YS, Altstiel L, Bender M, Hyslop P, Johnstone EM, Little SP, Cummins DJ, Piccardo P, Ghetti B, Paul SM (1997) Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition. Nat Gen 17:263–264Google Scholar
  10. Bales KR, Verina T, Cummins DJ, Du Y, Dodel RC, Saura J, Fishman CE, DeLong CA, Piccardo P, Petegnief V, Ghetti B, Paul SM (1999) Apolipoprotein E is essential for amyloid deposition in the APPV717F transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 96:15233–15238PubMedGoogle Scholar
  11. Bales KR, Liu F, Wu S, Lin S, Koger D, DeLong C, Hansen JC, Sullivan PM, Paul SM (2009) Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice. J Neurosci 29:6771–6779PubMedGoogle Scholar
  12. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of alzheimer disease. Nat Med 6:916–919PubMedGoogle Scholar
  13. Baumann K, Mandelkow EM, Biernat J, Piwnica-Worms H, Mandelkow E (1993) Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett 336:417–424PubMedGoogle Scholar
  14. Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR, Jenkins L, Millais SB, Donoghue S (2005) Evaluation of the safety and immunogenicity of synthetic Aβ42 (AN1792) in patients with AD. Neurology 64:94–101PubMedGoogle Scholar
  15. Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45:675–688PubMedGoogle Scholar
  16. Biran Y, Masters CL, Barnham KJ, Bush AI, Adlard PA (2009) Pharmacotherapeutic targets in Alzheimer’s disease. J Cell Mol Med 13:61–86PubMedGoogle Scholar
  17. Blurton-Jones M, LaFerla FM (2006) Pathways by which Abeta facilitates tau pathology. Curr Alzheimer Res 3:437–448PubMedGoogle Scholar
  18. Boche D, Nicoll JA (2008) The role of the immune system in clearance of Abeta from the brain. Brain Pathol 18:267–278PubMedGoogle Scholar
  19. Bolmont T, Clavaguera F, Meyer-Luehmann M, Herzig MC, Radde R, Staufenbiel M, Lewis J, Hutton M, Tolnay M, Jucker M (2007) Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP × Tau transgenic mice. Am J Pathol 171:2012–2020PubMedGoogle Scholar
  20. Bombois S, Maurage CA, Gompel M, Deramecourt V, kowiak-Cordoliani MA, Black RS, Lavielle R, Delacourte A, Pasquier F (2007) Absence of beta-amyloid deposits after immunization in Alzheimer disease with Lewy body dementia. Arch Neurol 64:583–587PubMedGoogle Scholar
  21. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro and in vivo. Neuron 17:1005–1013PubMedGoogle Scholar
  22. Borchelt DR, Ratovitski T, Van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939–945PubMedGoogle Scholar
  23. Boutajangout A, Frangione B, Brion JP, Wisniewski T, Sigurdsson EM (2008) Presenilin 1mutation promotes tau phosphorylation and aggregation in a novel Alzheimer’s disease mouse model. Alz Dement 4:T185Google Scholar
  24. Boutajangout A, Goni F, Knudsen E, Schreiber F, Asuni A, Quartermain D, Frangione B, Chabalgoity A, Wisniewski T, Sigurdsson EM (2009) Diminished amyloid-beta burden in Tg2576 mice following a prophylactic oral immunization with a Salmonella-based amyloid-beta derivative vaccine. J Alzheimers Dis [Epub ahead of print]Google Scholar
  25. Brion JP (2006) Immunological demonstration of tau protein in neurofibrillary tangles of Alzheimer’s disease. J Alzheimers Dis 9:177–185PubMedGoogle Scholar
  26. Brion JP, Flament-Durand J, Dustin P (1986) Alzheimer’s disease and tau proteins. Lancet 2:1098PubMedGoogle Scholar
  27. Brody DL, Holtzman DM (2008) Active and passive immunotherapy for neurodegenerative diseass. Annu Rev Neurosci 31:175–193PubMedGoogle Scholar
  28. Brouwers N, Sleegers K, Van BC (2008) Molecular genetics of Alzheimer’s disease: an update. Ann Med 40:562–583PubMedGoogle Scholar
  29. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33:95–130PubMedGoogle Scholar
  30. Butner KA, Kirschner MW (1991) Tau protein binds to microtubules through a flexible array of distributed weak sites. J Cell Biol 115:717–730PubMedGoogle Scholar
  31. Butovsky O, Kunis G, Koronyo-Hamaoui M, Schwartz M (2007) Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in a mouse Alzheimer’s disease model. Eur J Neurosci 26:413–416PubMedGoogle Scholar
  32. Calhoun ME, Wiederhold KH, Abramowski D, Phinney AL, Probst A, Sturchler-Pierrat C, Staufenbiel M, Sommer B, Jucker M (1998) Neuron loss in APP transgenic mice. Nature 396:755–756Google Scholar
  33. Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem N Jr, Ashe KH, Frautschy SA, Cole GM (2004) Docosahexaenoic acid protects from dendritic pathology in an Alzheimer’s disease mouse model. Neuron 43:633–645PubMedGoogle Scholar
  34. Casas C, Sergeant N, Itier JM, Blanchard V, Wirths O, van der Kolk N, Vingtdeux V, van de SE, Ret G, Canton T, Drobecq H, Clark A, Bonici B, Delacourte A, Benavides J, Schmitz C, Tremp G, Bayer TA, Benoit P, Pradier L (2004) Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol 165:1289–1300Google Scholar
  35. Castellani RJ, Lee HG, Zhu X, Perry G, Smith MA (2008) Alzheimer disease pathology as a host response. J Neuropathol Exp Neurol 67:523–531PubMedGoogle Scholar
  36. Chackerian B, Rangel M, Hunter Z, Peabody DS (2006) Virus and virus-like particle-based immunogens for Alzheimer’s disease induce antibody responses against amyloid-beta without concomitant T cell responses. Vaccine 24:6321–6331PubMedGoogle Scholar
  37. Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, Strome R, Zuker N, Loukides J, French J, Turner S, Lozza G, Grilli M, Kunicki S, Morissette C, Paquette J, Gervais F, Bergeron C, Fraser PE, Carlson GA, George-Hyslop PS, Westaway D (2001) Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem 276:21562–21570PubMedGoogle Scholar
  38. Citron M, Westaway D, Xia WM, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, Hyslop PS, Selkoe DJ (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat Med 3:67–72PubMedGoogle Scholar
  39. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11(3):909–913Google Scholar
  40. Colton CA, Vitek MP, Wink DA, Xu Q, Cantillana V, Previti ML, van Nostrand WE, Weinberg JB, Dawson H (2006) NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 103:12867–12872PubMedGoogle Scholar
  41. Cribbs DH, Ghochikyan A, Vasilevko V, Tran M, Petrushina I, Sadzikava N, Babikyan D, Kesslak P, Kieber-Emmons T, Cotman CW, Agadjanyan MG (2003) Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid. Int Immunol 15:505–514PubMedGoogle Scholar
  42. Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, Zlokovic BV, van Nostrand WE (2004) Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor. J Biol Chem 279:20296–20306PubMedGoogle Scholar
  43. Davis J, Xu F, Miao J, Previti ML, Romanov G, Ziegler K, van Nostrand WE (2006) Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double A beta in human A betaPP transgenic mice. Neurobiol Aging 27:946–954PubMedGoogle Scholar
  44. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM (2001) Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 98:8850–8855PubMedGoogle Scholar
  45. Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM (2002) Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci 5:452–457PubMedGoogle Scholar
  46. Domnitz SB, Robbins EM, Hoang AW, Garcia-Alloza M, Hyman BT, Rebeck GW, Greenberg SM, Bacskai BJ, Frosch MP (2005) Progression of cerebral amyloid angiopathy in transgenic mouse models of Alzheimer disease. J Neuropathol Exp Neurol 64:588–594PubMedGoogle Scholar
  47. Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-Tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S (1996) Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1. Nature 383:710–713PubMedGoogle Scholar
  48. Dziewczapolski G, Glogowski CM, Masliah E, Heinemann SF (2009) Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer’s disease. J Neurosci 29:8805–8815PubMedGoogle Scholar
  49. Egashira N, Iwasaki K, Takashima A, Watanabe T, Kawabe H, Matsuda T, Mishima K, Chidori S, Nishimura R, Fujiwara M (2005) Altered depression-related behavior and neurochemical changes in serotonergic neurons in mutant R406 W human tau transgenic mice. Brain Res 1059:7–12PubMedGoogle Scholar
  50. Eidenmuller J, Fath T, Maas T, Pool M, Sontag E, Brandt R (2001) Phosphorylation-mimicking glutamate clusters in the proline-rich region are sufficient to simulate the functional deficiencies of hyperphosphorylated tau protein. Biochem J 357:759–767PubMedGoogle Scholar
  51. Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX, Roth K, Aguzzi A, Staufenbiel M, Walker LC, Jucker M (2009) Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci USA 106:12926–12931PubMedGoogle Scholar
  52. El KJ, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13:432–438Google Scholar
  53. Fath T, Eidenmuller J, Brandt R (2002) Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer’s disease. J Neurosci 22:9733–9741PubMedGoogle Scholar
  54. Ferrer I, Boada RM, Sanchez Guerra ML, Rey MJ, Costa-Jussa F (2004) Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol 14:11–20PubMedGoogle Scholar
  55. Frackowiak J, Wisniewski HM, Wegiel J, Merz GS, Iqbal K, Wang KC (1992) Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol 84:225–233PubMedGoogle Scholar
  56. Frautschy SA, Yang F, Irrizarry M, Hyman B, Saido TC, Hsiao K, Cole GM (1998) Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 152:307–317PubMedGoogle Scholar
  57. Frenkel D, Dewachter I, Van LF, Solomon B (2003) Reduction of beta-amyloid plaques in brain of transgenic mouse model of Alzheimer’s disease by EFRH-phage immunization. Vaccine 21:1060–1065PubMedGoogle Scholar
  58. Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852PubMedGoogle Scholar
  59. Fryer JD, Taylor JW, DeMattos RB, Bales KR, Paul SM, Parsadanian M, Holtzman DM (2003) Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein Transgenic mice. J Neurosci 23:7889–7896PubMedGoogle Scholar
  60. Fryer JD, Simmons K, Parsadanian M, Bales KR, Paul SM, Sullivan PM, Holtzman DM (2005) Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci 25:2803–2810PubMedGoogle Scholar
  61. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, Guido T, Hagoplan S, Johnson-Wood K, Kan K, Lee M, Leibowitz P, Lieberburg I, Little S, Masliah E, McConlogue L, Montoya-Zavala M, Mucke L, Paganini L, Penniman E, Power M, Schenk D, Seubert P, Snyder B, Soriano F, Tan H, Vitale J, Wadsworth S, Wolozin B, Zhao J (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373:523–527PubMedGoogle Scholar
  62. Gendron TF, Petrucelli L (2009) The role of tau in neurodegeneration. Mol Neurodegener 4:13PubMedGoogle Scholar
  63. Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Boada Rovira M, Forette F, Orgogozo JM (2005) Clinical effects of Aβ immunization (AN1792) in patients with AD in an interupted trial. Neurol 64:1553–1562Google Scholar
  64. Giuffrida ML, Caraci F, Pignataro B, Cataldo S, De BP, Bruno V, Molinaro G, Pappalardo G, Messina A, Palmigiano A, Garozzo D, Nicoletti F, Rizzarelli E, Copani A (2009) Beta-amyloid monomers are neuroprotective. J Neurosci 29:10582–10587PubMedGoogle Scholar
  65. Glabe CG (2008) Structural classification of toxic amyloid oligomers. J Biol Chem 283:29639–29643PubMedGoogle Scholar
  66. Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci USA 85:4051–4055PubMedGoogle Scholar
  67. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3:519–526PubMedGoogle Scholar
  68. Goni F, Prelli F, Schreiber F, Scholtzova H, Chung E, Kascsak R, Brown DR, Sigurdsson EM, Chabalgoity JA, Wisniewski T (2008) High titers of mucosal and systemic anti-PrP antibodies abrogates oral prion infection in mucosal vaccinated mice. Neurosci. 153:679–686Google Scholar
  69. Gotz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9:532–544PubMedGoogle Scholar
  70. Gotz J, Barmettler R, Ferrari A, Goedert M, Probst A, Nitsch RM (2000) In vivo analysis of wild-type and FTDP-17 tau transgenic mice. Ann N Y Acad Sci 920:126–133PubMedGoogle Scholar
  71. Gotz J, Chen F, Barmettler R, Nitsch RM (2001a) Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem 276:529–534PubMedGoogle Scholar
  72. Gotz J, Chen F, van Dorpe J, Nitsch RM (2001b) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–1495Google Scholar
  73. Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM (2001) Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol 49:697–705PubMedGoogle Scholar
  74. Hamdane M, Sambo AV, Delobel P, Begard S, Violleau A, Delacourte A, Bertrand P, Benavides J, Buee L (2003) Mitotic-like tau phosphorylation by p25-Cdk5 kinase complex. J Biol Chem 278:34026–34034PubMedGoogle Scholar
  75. Hara H, Monsonego A, Yuasa K, Adachi Y, Xiao X, Takeda S, Takahashi K, Weiner HL, Tabira T (2004) Development of a safe oral Ab vaccine using recombinant adeno-associated virus vector for Alzheimer’s disease. J Alzheimers Dis 6:483–488PubMedGoogle Scholar
  76. Hardy J (2006) A hundred years of Alzheimer’s disease research. Neuron 52:3–13PubMedGoogle Scholar
  77. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356PubMedGoogle Scholar
  78. Head E, Pop V, Vasilevko V, Hill M, Saing T, Sarsoza F, Nistor M, Christie LA, Milton S, Glabe C, Barrett E, Cribbs D (2008) A two-year study with fibrillar beta-amyloid (Abeta) immunization in aged canines: effects on cognitive function and brain Abeta. J Neurosci 28:3555–3566PubMedGoogle Scholar
  79. Hock C, Konietzko U, Paspassotiropoulos A, Wollmer A, Streffer J, von Rotz RC, Davey G, Moritz E, Nitsch RM (2002) Generation of antibodies specific for β-amyloid by vaccination of patients with Alzheimer disease. Nat Med 8:1270–1276PubMedGoogle Scholar
  80. Hock C, Konietzko U, Straffer JR, Tracy J, Signorell A, Muller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia E, Axel Wollmar M, Umbricht D, de Quervain DJF, Hofmann M, Maddalena A, Papassotiropoulos A, Nitsch RM (2003) Antibodies against β-amyloid slow cognitive decline in Alzheimer’s disease. Neuron 38:547–554PubMedGoogle Scholar
  81. Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Saad WK, Mueller R, Morgan D, Sanders S, Zehr C, O’Campo K, Hardy J, Prada CM, Eckman C, Younkin S, Hsiao K, Duff K (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4:97–100PubMedGoogle Scholar
  82. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JAR (2008) Long term effects of Aβ42 immunization in Alzheimer’s disease: immune response, plaque removal and clinical function. Lancet 372:216–223PubMedGoogle Scholar
  83. Holtzman DM, Bales KR, Wu S, Bhat P, Parsadanian M, Fagan AM, Chang LK, Sun Y, Paul SM (1999) Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer’s disease. J Clin Invest 103:R15–R21PubMedGoogle Scholar
  84. Holtzman DM, Fagan AM, Mackey B, Tenkova T, Sartorius L, Paul SM, Bales KR, Hsiao Ashe K, Irizarry MC, Hyman BT (2000) Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol 47:739–747PubMedGoogle Scholar
  85. Hsiao KK, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Aβ elevation and amyloid plaques in transgenic mice. Science 274:99–102PubMedGoogle Scholar
  86. Iqbal K, Liu F, Gong CX, Alonso AC, Grundke-Iqbal I (2009) Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 118:53–69PubMedGoogle Scholar
  87. Irizarry MC, McNamara M, Fedorchak K, Hsiao K, Hyman BT (1997a) APPSw transgenic mice develop age-related Aβ deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol 56:965–973PubMedGoogle Scholar
  88. Irizarry MC, Soriano F, McNamara M, Page KJ, Schenk D, Games D, Hyman BT (1997b) Aβ deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci 17:7053–7059PubMedGoogle Scholar
  89. Ishihara T, Zhang B, Higuchi K, Yoshiyama Y, Trojanowski JQ, Lee VM (2001) Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice. Am J Pathol 158:555–562PubMedGoogle Scholar
  90. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, George-Hyslop P, Westaway D (2000) Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 408:979–982PubMedGoogle Scholar
  91. Jellinger KA (2002) Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 109:813–836PubMedGoogle Scholar
  92. Jennings GT, Bachmann MF (2008) The coming of age of virus-like particle vaccines. Biol. Chem. 389:521–536PubMedGoogle Scholar
  93. Jucker M, Heppner FL (2008) Cerebral and peripheral amyloid phagocytes—an old liaison with a new twist. Neuron 59:8–10PubMedGoogle Scholar
  94. Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG (2001) Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci 21:372–381PubMedGoogle Scholar
  95. Kayed R, Jackson GR (2009) Prefilament tau species as potential targets for immunotherapy for Alzheimer disease and related disorders. Curr Opin Immunol 21:359–363PubMedGoogle Scholar
  96. Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63:287–303PubMedGoogle Scholar
  97. King ME, Kan HM, Baas PW, Erisir A, Glabe CG, Bloom GS (2006) Tau-dependent microtubule disassembly initiated by prefibrillar beta-amyloid. J Cell Biol 175:541–546PubMedGoogle Scholar
  98. Klybin I, Betts V, Blennow K, Zetterberg H, Wallin A, Lemere CA, Cullen WK, Welzel A, Peng Y, Wisniewski T, Selkoe DJ, Anwyl R, Walsh DM, Rowan MJ (2008) Aβ dimer-containing human cerebrospinal fluid disrupts synaptic plasticity: prevention by systemic passive immunization. J Neurosci 28:4231–4237Google Scholar
  99. Kok E, Haikonen S, Luoto T, Huhtala H, Goebeler S, Haapasalo H, Karhunen PJ (2009) Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann Neurol 65:650–657PubMedGoogle Scholar
  100. Kramer JH, Reed BR, Mungas D, Weiner MW, Chui HC (2002) Executive dysfunction in subcortical ischaemic vascular disease. J Neurol Neurosurg Psychiatry 72:217–220PubMedGoogle Scholar
  101. Kumar-Singh S (2009) Hereditary and sporadic forms of abeta-cerebrovascular amyloidosis and relevant transgenic mouse models. Int J Mol Sci 10:1872–1895PubMedGoogle Scholar
  102. Kumar-Singh S, Dewachter I, Moechars D, Lubke U, De JC, Ceuterick C, Checler F, Naidu A, Cordell B, Cras P, Van BC, Van LF (2000) Behavioral disturbances without amyloid deposits in mice overexpressing human amyloid precursor protein with Flemish (A692G) or Dutch (E693Q) mutation. Neurobiol Dis 7:9–22PubMedGoogle Scholar
  103. Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN, Khuon D, Gong Y, Bigio EH, Shaw P, De Felice FG, Krafft GA, Klein WL (2007) Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem 100:23–35PubMedGoogle Scholar
  104. Lambert MP, Velasco PT, Viola KL, Klein WL (2009) Targeting generation of antibodies specific to conformational epitopes of amyloid beta-derived neurotoxins. CNS. Neurol Disord Drug Targets 8:65–81Google Scholar
  105. Lavie V, Becker M, Cohen-Kupiec R, Yacoby I, Koppel R, Wedenig M, Hutter-Paier B, Solomon B (2004) EFRH-phage immunization of Alzheimer’s disease animal model improves behavioral performance in morris water maze trials. J Mol Neurosci 24:105–114PubMedGoogle Scholar
  106. Lee VM, Kenyon TK, Trojanowski JQ (2005) Transgenic animal models of tauopathies. Biochim Biophys Acta 1739:251–259PubMedGoogle Scholar
  107. Lee EB, Leng LZ, Zhang B, Kwong L, Trojanowski JQ, Abel T, Lee VM (2006) Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice. J Biol Chem 281:4292–4299PubMedGoogle Scholar
  108. Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ (1996) Sequence of deposition of heterogeneous amyloid β-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 3:16–32PubMedGoogle Scholar
  109. Lemere CA, Maron R, Selkoe DJ, Weiner HL (2001) Nasal vaccination with beta-amyloid peptide for the treatment of Alzheimer’s disease. DNA Cell Biol 20:705–711PubMedGoogle Scholar
  110. Lemere CA, Spooner ET, Leverone JF, Mori C, Clements JD (2002) Intranasal immunotherapy for the treatment of Alzheimer’s disease: Escherichia coli LT and LT(R192G) as mucosal adjuvants. Neurobiol Aging 23:991–1000PubMedGoogle Scholar
  111. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352–357PubMedGoogle Scholar
  112. Levites Y, Das P, Price RW, Rochette MJ, Kostura LA, McGowan EM, Murphy MP, Golde TE (2006) Anti-Aβ42 and anti-Aβ40 specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model. J Clin Invest 116:193–201PubMedGoogle Scholar
  113. Levy E, Carman MD, Fernandez-Madrid I, Lieberburg I, Power MD, van Duinen SG, Bots GThAM, Luyendijk W, Frangione B (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248:1124–1126PubMedGoogle Scholar
  114. Lewis J, Dickson D, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491PubMedGoogle Scholar
  115. Magnani E, Fan J, Gasparini L, Golding M, Williams M, Schiavo G, Goedert M, Amos LA, Spillantini MG (2007) Interaction of tau protein with the dynactin complex. EMBO J 26:4546–4554PubMedGoogle Scholar
  116. Mahley RW, Huang Y (2009) Alzheimer disease: multiple causes, multiple effects of apolipoprotein E4, and multiple therapeutic approaches. Ann Neurol 65:623–625PubMedGoogle Scholar
  117. Maier M, Seabrook TJ, Lazo ND, Jiang L, Das P, Janus C, Lemere CA (2006) Short amyloid-beta (Abeta) immunogens reduce cerebral Abeta load and learning deficits in an Alzheimer’s disease mouse model in the absence of an Abeta-specific cellular immune response. J Neurosci 26:4717–4728PubMedGoogle Scholar
  118. Mamikonyan G, Necula M, Mkrtichyan M, Ghochikyan A, Petrushina I, Movsesyan N, Mina E, Kiyatkin A, Glabe CG, Cribbs DH, Agadjanyan MG (2007) Anti-A beta 1–11 antibody binds to different beta-amyloid species, inhibits fibril formation, and disaggregates preformed fibrils but not the most toxic oligomers. J Biol Chem 282:22376–22386PubMedGoogle Scholar
  119. Masliah E, Sisk A, Mallory M, Games D (2001) Neurofibrillary pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. J Neuropathol Exp Neurol 60:357–368PubMedGoogle Scholar
  120. Masliah E, Hansen L, Adame A, Crews L, Bard F, Lee C, Seubert P, Games D, Kirby L, Schenk D (2005a) Aβ vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64:129–131PubMedGoogle Scholar
  121. Masliah E, Rockenstein E, Adame A, Alford M, Crews L, Hashimoto M, Seubert P, Lee M, Goldstein J, Chilcote T, Games D, Schenk D (2005b) Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. Neuron 46:857–868PubMedGoogle Scholar
  122. McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, Skipper L, Murphy MP, Beard J, Das P, Jansen K, Delucia M, Lin WL, Dolios G, Wang R, Eckman CB, Dickson DW, Hutton M, Hardy J, Golde T (2005) Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47:191–199PubMedGoogle Scholar
  123. McGowan E, Eriksen J, Hutton M (2006) A decade of modeling Alzheimer’s disease in transgenic mice. Trends Genet 22:281–289PubMedGoogle Scholar
  124. McKee AC, Carreras I, Hossain L, Ryu H, Klein WL, Oddo S, LaFerla FM, Jenkins BG, Kowall NW, Dedeoglu A (2008) Ibuprofen reduces Abeta, hyperphosphorylated tau and memory deficits in Alzheimer mice. Brain Res 1207:225–236PubMedGoogle Scholar
  125. McLaurin J, Cecal R, Kierstead ME, Tian X, Phinney AL, Manea M, French JE, Lambermon MH, Darabie AA, Brown ME, Janus C, Chishti MA, Horne P, Westaway D, Fraser PE, Mount HT, Przybylski M, St George-Hyslop P (2002) Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4–10 and inhibit cytotoxicity and fibrillogenesis. Nat Med 8:1263–1269PubMedGoogle Scholar
  126. Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784PubMedGoogle Scholar
  127. Moechars D, Dewachter I, Lorent K, Reverse D, Baekelandt V, Naidu A, Tesseur I, Spittaels K, Haute CV, Checler F, Godaux E, Cordell B, Van LF (1999) Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem 274:6483–6492PubMedGoogle Scholar
  128. Moretto N, Bolchi A, Rivetti C, Imbimbo BP, Villetti G, Pietrini V, Polonelli L, Del SS, Smith KM, Ferrante RJ, Ottonello S (2007) Conformation-sensitive antibodies against alzheimer amyloid-beta by immunization with a thioredoxin-constrained B-cell epitope peptide. J Biol Chem 282:11436–11445PubMedGoogle Scholar
  129. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW (2000) Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408(6815):982–985PubMedGoogle Scholar
  130. Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Watanabe A, Titani K, Ihara Y (1995) Hyperphosphorylation of tau in PHF. Neurobiol Aging 16:365–371PubMedGoogle Scholar
  131. Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan H, Olkhanud PB, Head E, Biragyn A, Cribbs DH, Agadjanyan MG (2008) Reducing AD-like pathology in 3× Tg-AD mouse model by DNA epitope vaccine—a novel immunotherapeutic strategy. PLoS ONE 3:e2124PubMedGoogle Scholar
  132. Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L (2000) High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–4058PubMedGoogle Scholar
  133. Murakami T, Paitel E, Kawarabayashi T, Ikeda M, Chishti MA, Janus C, Matsubara E, Sasaki A, Kawarai T, Phinney AL, Harigaya Y, Horne P, Egashira N, Mishima K, Hanna A, Yang J, Iwasaki K, Takahashi M, Fujiwara M, Ishiguro K, Bergeron C, Carlson GA, Abe K, Westaway D, St George-Hyslop P, Shoji M (2006) Cortical neuronal and glial pathology in TgTauP301L transgenic mice: neuronal degeneration, memory disturbance, and phenotypic variation. Am J Pathol 169:1365–1375PubMedGoogle Scholar
  134. Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, Buxbaum JD (2000) Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283:1571–1577PubMedGoogle Scholar
  135. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO (2005) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9:448–452Google Scholar
  136. Nicoll JA, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, Vlachouli C, Wilkinson D, Bayer A, Games D, Seubert P, Schenk D, Holmes C (2006) Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol 65:1040–1048PubMedGoogle Scholar
  137. Nikolic WV, Bai Y, Obregon D, Hou H, Mori T, Zeng J, Ehrhart J, Shytle RD, Giunta B, Morgan D, Town T, Tan J (2007) Transcutaneous beta-amyloid immunization reduces cerebral beta-amyloid deposits without T cell infiltration and microhemorrhage. Proc Natl Acad Sci USA 104:2507–2512PubMedGoogle Scholar
  138. Noble W, Garwood CJ, Hanger DP (2009) Minocycline as a potential therapeutic agent in neurodegenerative disorders characterised by protein misfolding. Prion 3(2):78–83Google Scholar
  139. Obregon D, Hou H, Bai Y, Nikolic WV, Mori T, Luo D, Zeng J, Ehrhart J, Fernandez F, Morgan D, Giunta B, Town T, Tan J (2008) CD40L disruption enhances Abeta vaccine-mediated reduction of cerebral amyloidosis while minimizing cerebral amyloid angiopathy and inflammation. Neurobiol Dis 29:336–353PubMedGoogle Scholar
  140. Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM (2003a) Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease 6. Neurobiol Aging 24:1063–1070PubMedGoogle Scholar
  141. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003b) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421PubMedGoogle Scholar
  142. Oddo S, Caccamo A, Tran L, Lambert MP, Glabe CG, Klein WL, LaFerla FM (2006) Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem 281:1599–1604PubMedGoogle Scholar
  143. Pappolla MA, Chyan YJ, Omar RA, Hsiao K, Perry G, Smith MA, Bozner P (1998) Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer’s disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo. Am J Pathol 152:871–877PubMedGoogle Scholar
  144. Petrushina I, Ghochikyan A, Mkrtichyan M, Mamikonyan G, Movsesyan N, Ajdari R, Vasilevko V, Karapetyan A, Lees A, Agadjanyan MG, Cribbs DH (2008) Mannan-Abeta28 conjugate prevents Abeta-plaque deposition, but increases microhemorrhages in the brains of vaccinated Tg2576 (APPsw) mice. J Neuroinflamm 5:42Google Scholar
  145. Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ (2002a) Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology 58:1629–1634PubMedGoogle Scholar
  146. Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M (2002b) Cerebral hemorrhage after passive anti-Aβ immunotherapy. Science 298:1379PubMedGoogle Scholar
  147. Prelli F, Castaño EM, Glenner GG, Frangione B (1988) Differences between vascular and plaque core amyloid in Alzheimer’s disease. J Neurochem 51:648–651PubMedGoogle Scholar
  148. Pride M, Seubert P, Grundman M, Hagen M, Eldridge J, Black RS (2008) Progress in the active immunotherapeutic approach to Alzheimer’s disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis 5:194–196PubMedGoogle Scholar
  149. Puzzo D, Privitera L, Leznik E, Fa M, Staniszewski A, Palmeri A, Arancio O (2008) Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 28:14537–14545PubMedGoogle Scholar
  150. Racke MM, Boone LI, Hepburn DL, Parsadanian M, Bryan MT, Ness DK, Piroozi KS, Jordan WH, Brown DD, Hoffman WP, Holtzman DM, Bales KR, Gitter BD, May PC, Paul SM, DeMattos RB (2005) Exacerbation of cerebral amyloid angiopathy-associated microhemorrhages in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyoid beta. J Neurosci 25:629–636PubMedGoogle Scholar
  151. Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Calhoun ME, Jaggi F, Wolburg H, Gengler S, Haass C, Ghetti B, Czech C, Holscher C, Mathews PM, Jucker M (2006) Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 7:940–946PubMedGoogle Scholar
  152. Rafii MS, Aisen PS (2009) Recent developments in Alzheimer’s disease therapeutics. BMC Med 7:7PubMedGoogle Scholar
  153. Reiman EM, Caselli RJ, Yun LS, Chen KW, Bandy D, Minoshima S, Thibodeau SN, Osborne D (1996) Preclinical evidence of Alzheimer’s disease in persons homozygous for the ε4 allele for apolipoprotein E. N Engl J Med 334:752–758PubMedGoogle Scholar
  154. Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J (2004) Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci USA 101:284–289PubMedGoogle Scholar
  155. Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Keppler J, Reeder SA, Langbaum JB, Alexander GE, Klunk WE, Mathis CA, Price JC, Aizenstein HJ, DeKosky ST, Caselli RJ (2009) Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proc Natl Acad Sci USA 106:6820–6825PubMedGoogle Scholar
  156. Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR (2009) Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol 11:219–225PubMedGoogle Scholar
  157. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–754PubMedGoogle Scholar
  158. Rockenstein E, Mallory M, Mante M, Sisk A, Masliaha E (2001) Early formation of mature amyloid-beta protein deposits in a mutant APP transgenic model depends on levels of Abeta(1–42). J Neurosci Res 66:573–582PubMedGoogle Scholar
  159. Sadowski M, Wisniewski T (2007) Disease modifying approaches for Alzheimer’s pathology. Curr Pharm Des 13:1943–1954PubMedGoogle Scholar
  160. Sadowski M, Pankiewicz J, Scholtzova H, Mehta P, Prelli F, Quartermain D, Wisniewski T (2006) Blocking the apolipoproteinE/Amyloid β interaction reduces the parenchymal and vascular amyloid-β deposition and prevents memory deficit in AD transgenic mice. Proc Natl Acad Sci USA 103:18787–18792PubMedGoogle Scholar
  161. Sadowski M, Verma A, Wisniewski T (2008) Infectious disease of the nervous system: prion diseases. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J (eds) Neurology in clinical practice. Elsevier, Philadelphia, pp 1567–1581Google Scholar
  162. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid-β attenuates Alzheimer disease-like pathology in the PDAPP mice. Nature 400:173–177PubMedGoogle Scholar
  163. Schiltz JG, Salzer U, Mohajeri MH, Franke D, Heinrich J, Pavlovic J, Wollmer MA, Nitsch RM, Moelling K (2004) Antibodies from a DNA peptide vaccination decrease the brain amyloid burden in a mouse model of Alzheimer’s disease. J Mol Med 82:706–714PubMedGoogle Scholar
  164. Schindowski K, Bretteville A, Leroy K, Begard S, Brion JP, Hamdane M, Buee L (2006) Alzheimer’s disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol 169:599–616PubMedGoogle Scholar
  165. Scholtzova H, Kascsak RJ, Bates KA, Boutajangout A, Kerr DJ, Meeker HC, Mehta PD, Spinner DS, Wisniewski T (2009) Induction of Toll-like receptor 9 signaling as a method for ameliorating Alzheimer’s disease related pathology. J Neurosci 29:1846–1854PubMedGoogle Scholar
  166. Seabrook TJ, Thomas K, Jiang L, Bloom J, Spooner E, Maier M, Bitan G, Lemere CA (2006) Dendrimeric Abeta1-15 is an effective immunogen in wild-type and APP-tg mice. Neurobiol Aging 28(6):813–823PubMedGoogle Scholar
  167. Sergeant N, David JP, Lefranc D, Vermersch P, Wattez A, Delacourte A (1997) Different distribution of phosphorylated tau protein isoforms in Alzheimer’s and Pick’s diseases. FEBS Lett. 412:578–582PubMedGoogle Scholar
  168. Sergeant N, Bretteville A, Hamdane M, Caillet-Boudin ML, Grognet P, Bombois S, Blum D, Delacourte A, Pasquier F, Vanmechelen E, Schraen-Maschke S, Buee L (2008) Biochemistry of Tau in Alzheimer’s disease and related neurological disorders. Expert. Rev. Proteomics. 5:207–224PubMedGoogle Scholar
  169. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14(8):837–842PubMedGoogle Scholar
  170. Shioi J, Georgakopoulos A, Mehta P, Kouchi Z, Litterst CM, Baki L, Robakis NK (2007) FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem 101:674–681PubMedGoogle Scholar
  171. Sigurdsson EM (2008) Immunotherapy targeting pathological tau protein in Alzheimer’s disease and related tauopathies. J Alzheimers Dis 15:157–168PubMedGoogle Scholar
  172. Sigurdsson EM (2009) Tau-focused immunotherapy for Alzheimer’s disease and related tauopathies. Curr Alzheimer Res 6(5):446–450Google Scholar
  173. Sigurdsson EM, Scholtzova H, Mehta P, Frangione B, Wisniewski T (2001) Immunization with a nontoxic/nonfibrillar amyloid-β homologous peptide reduces Alzheimer’s disease-associated pathology in transgenic mice. Am J Pathol 159(2):439–447PubMedGoogle Scholar
  174. Sigurdsson EM, Frangione B, Wisniewski T (2002) Immunization for Alzheimer’s disease. Drug Dev Res 56:135–142Google Scholar
  175. Sigurdsson EM, Knudsen EL, Asuni A, Sage D, Goni F, Quartermain D, Frangione B, Wisniewski T (2004) An attenuated immune response is sufficient to enhance cognition in an Alzheimer’s disease mouse model immunized with amyloid-β derivatives. J Neurosci 24:6277–6282PubMedGoogle Scholar
  176. Small SA, Duff K (2008) Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron 60:534–542PubMedGoogle Scholar
  177. Smith MA, Hirai K, Hsiao K, Pappolla M, Harris PL, Siedlak SL, Tabaton M, Perry G (1998) Amyloid beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70:2212–2215PubMedCrossRefGoogle Scholar
  178. Solomon B (2007) Antibody-mediated immunotherapy for Alzheimer’s disease. Curr Opin Investig Drugs 8:519–524PubMedGoogle Scholar
  179. Solomon B, Koppel R, Frankel D, Hanan-Aharon E (1997) Disaggregation of Alzheimer β-amyloid by site-directed mAb. Proc Natl Acad Sci USA 94:4109–4112PubMedGoogle Scholar
  180. Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT (2005) Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy 7. J Neurosci 25:7278–7287PubMedGoogle Scholar
  181. Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Bürki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94:13287–13292PubMedGoogle Scholar
  182. Tagliavini F, Prelli F, Ghiso J, Bugiani O, Serban D, Prusiner SB, Farlow MR, Ghetti B, Frangione B (1991) Amyloid protein of Gerstmann-Straussler-Scheinker disease (Indiana kindred) is an 11 kd fragment of prion protein with an N- terminal glycine at codon 58. EMBO J 10:513–519PubMedGoogle Scholar
  183. Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi K (2006) Role of toll-like receptor signalling in Abeta uptake and clearance. Brain 129:3006–3019PubMedGoogle Scholar
  184. Takeuchi A, Irizarry MC, Duff K, Saido T, Hsiao Ashe K, Hasegawa H, Mann DM, Hyman BT, Iwatsubo T (2000) Age-related amyloid β deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid β precursor protein swedish mutant is not associated with global neuronal loss. Am J Pathol 157:331–339PubMedGoogle Scholar
  185. Tampellini D, Magrane J, Takahashi RH, Li F, Lin MT, Almeida CG, Gouras GK (2007) Internalized antibodies to the Abeta domain of APP reduce neuronal Abeta and protect against synaptic alterations. J Biol Chem 282:18895–18906PubMedGoogle Scholar
  186. Tan J, Town T, Paris D, Mori T, Suo Z, Crawford F, Mattson MP, Flavell RA, Mullan M (1999) Microglial activation resulting from CD40–CD40L interaction after beta-amyloid stimulation. Science 286:2352–2355PubMedGoogle Scholar
  187. Tanemura K, Akagi T, Murayama M, Kikuchi N, Murayama O, Hashikawa T, Yoshiike Y, Park JM, Matsuda K, Nakao S, Sun X, Sato S, Yamaguchi H, Takashima A (2001) Formation of filamentous tau aggregations in transgenic mice expressing V337M human tau. Neurobiol Dis 8:1036–1045PubMedGoogle Scholar
  188. Taniguchi T, Doe N, Matsuyama S, Kitamura Y, Mori H, Saito N, Tanaka C (2005) Transgenic mice expressing mutant (N279 K) human tau show mutation dependent cognitive deficits without neurofibrillary tangle formation. FEBS Lett. 579:5704–5712PubMedGoogle Scholar
  189. Tanzi RE, Bertram L (2005) Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 120:545–555PubMedGoogle Scholar
  190. Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, Duman RS, Flavell RA (2008) Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 14:681–687PubMedGoogle Scholar
  191. Tsai J, Grutzendler J, Duff K, Gan WB (2004) Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 7:1181–1183PubMedGoogle Scholar
  192. Utton MA, Noble WJ, Hill JE, Anderton BH, Hanger DP (2005) Molecular motors implicated in the axonal transport of tau and alpha-synuclein. J Cell Sci 118:4645–4654PubMedGoogle Scholar
  193. Vermeer SE, Den Heijer T, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MM (2003) Incidence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke 34:392–396Google Scholar
  194. Vidal R, Frangione B, Rostagno A, Mead S, Revesz T, Plant G, Ghiso J (1999) A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 399:776–781PubMedGoogle Scholar
  195. Vidal R, Revesz T, Rostagno A, Kim E, Holton JL, Bek T, Bojsen-Moller M, Braendgaard H, Plant G, Ghiso J, Frangione B (2000) A decamer duplication in the 3’ region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. Proc Natl Acad Sci USA 97:4920–4925PubMedGoogle Scholar
  196. Wang JZ, Liu F (2008) Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol 85:148–175PubMedGoogle Scholar
  197. Weiner HL, Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, Issazadeh S, Hancock WW, Selkoe D (2000) Nasal administration of amyloid-β peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease. Ann Neurol 48:567–579PubMedGoogle Scholar
  198. Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D (2004) Passive immunization against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J. Neuroinflammation 1:24PubMedGoogle Scholar
  199. Wilcock DM, Jantzen PT, Li Q, Morgan D, Gordon MN (2007) Amyloid-beta vaccination, but not nitro-nonsteroidal anti-inflammatory drug treatment, increases vascular amyloid and microhemorrhage while both reduce parenchymal amyloid. Neuroscience 144:950–960PubMedGoogle Scholar
  200. Wilcock DM, Gharkholonarehe N, van Nostrand WE, Davis J, Vitek MP, Colton CA (2009a) Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer’s disease. J Neurosci 29:7957–7965PubMedGoogle Scholar
  201. Wilcock DM, Vitek MP, Colton CA (2009b) Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer’s disease. Neuroscience 159:1055–1069PubMedGoogle Scholar
  202. Wilhelmus MM, de Waal RM, Verbeek MM (2007) Heat shock proteins and amateur chaperones in amyloid-Beta accumulation and clearance in Alzheimer’s disease. Mol Neurobiol 35:203–216PubMedGoogle Scholar
  203. Wisniewski T (2005) Practice point commentary on “Clinical effects of Aβ immunization (AN1792) in patients with AD in an interupted trial”. Nat Clin Pract Neurol 1:84–85Google Scholar
  204. Wisniewski T, Boutajangout A (2009) Vaccination as a therapeutic approach for Alzheimer’s disease. Mount Sinai J Med (in press)Google Scholar
  205. Wisniewski T, Frangione B (1992) Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett 135:235–238PubMedGoogle Scholar
  206. Wisniewski T, Frangione B (2005) Immunological and anti-chaperone therapeutic approaches for Alzheimer’s disease. Brain Pathol 15:72–77PubMedCrossRefGoogle Scholar
  207. Wisniewski T, Konietzko U (2008) Amyloid-β immunization for Alzheimer’s disease. Lancet Neurol 7:805–811PubMedGoogle Scholar
  208. Wisniewski T, Sadowski M (2008) Preventing Aβ fibrillization and deposition: β-sheet breakers and pathological chaperone inhibitors. BMC Neurosci 9:1–5Google Scholar
  209. Wisniewski T, Sigurdsson EM (2007) Therapeutic approaches for prion and Alzheimer’s diseases. FEBS J 274:3784–3798PubMedGoogle Scholar
  210. Wisniewski T, Golabek AA, Matsubara E, Ghiso J, Frangione B (1993) Apolipoprotein E: binding to soluble Alzheimer’s beta-amyloid. Biochem Biophys Res Commun 192:359–365PubMedGoogle Scholar
  211. Wisniewski T, Ghiso J, Frangione B (1994) Alzheimer’s disease and soluble Aβ. Neurobiol Aging 15:143–152PubMedGoogle Scholar
  212. Wisniewski T, Golabek AA, Kida E, Wisniewski KE, Frangione B (1995) Conformational mimicry in Alzheimer’s disease. Role of apolipoproteins in amyloidogenesis. Am J Pathol 147:238–244PubMedGoogle Scholar
  213. Wisniewski T, Prelli F, Scholtzova H, Chung E, Mehta PD, Kascsak R, Kascsak R, Goni F (2009) Immunotherapy targeting abnormal protein conformation. Alz. Dementia 4:113Google Scholar
  214. Wolfe MS (2009) Gamma-Secretase in biology and medicine. Semin. Cell Dev. Biol. 20:219–224PubMedGoogle Scholar
  215. Xu F, Grande AM, Robinson JK, Previti ML, Vasek M, Davis J, van Nostrand WE (2007) Early-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant amyloid beta-protein precursor transgenic mice. Neuroscience 146:98–107PubMedGoogle Scholar
  216. Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351PubMedGoogle Scholar
  217. Zamora E, Handisurya A, Shafti-Keramat S, Borchelt D, Rudow G, Conant K, Cox C, Troncoso JC, Kirnbauer R (2006) Papillomavirus-like particles are an effective platform for amyloid-beta immunization in rabbits and transgenic mice. J Immunol 177:2662–2670PubMedGoogle Scholar
  218. Zhang-Nunes SX, Maat-Schieman ML, Van Duinen SG, Roos RA, Frosch MP, Greenberg SM (2006) The cerebral beta-amyloid angiopathies: hereditary and sporadic. Brain Pathol 16:30–39PubMedGoogle Scholar
  219. Zilka N, Korenova M, Novak M (2009) Misfolded tau protein and disease modifying pathways in transgenic rodent models of human tauopathies. Acta Neuropathol 118:71–86PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of NeurologyNew York University School of MedicineNew YorkUSA
  2. 2.Department of PathologyNew York University School of MedicineNew YorkUSA
  3. 3.Department of Psychiatry, Millhauser LaboratoryNew York University School of MedicineNew YorkUSA

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