Drugs & Aging

, Volume 24, Issue 2, pp 107–119 | Cite as

Vaccination Strategies for Alzheimer’s Disease

A New Hope?
  • Adele WoodhouseEmail author
  • Tracey C. Dickson
  • James C. Vickers
Leading Article


The pathological hallmarks of Alzheimer’s disease (AD) include β-amyloid (Aβ) plaques, dystrophic neurites and neurofibrillary pathology, which eventually result in the degeneration of neurons and subsequent dementia. In 1999, international interest in a new therapeutic approach to the treatment of AD was ignited following transgenic mouse studies that indicated that it might be possible to immunise against the pathological alterations in Aβ that lead to aggregation of this protein in the brain. A subsequent phase I human trial for safety, tolerability and immunogenicity using an active immunisation strategy against Aβ had a positive outcome. However, phase ILA human trials involving active immunisation were halted following the diagnosis of aseptic meningoencephalitis in 6% of immunised subjects. Research into immunisation strategies involving transgenic AD mouse models has subsequently been refocused to determine the mechanisms by which plaque clearance and reduced memory deficits are attained, and to establish safer therapeutic approaches that may reduce potentially harmful brain inflammation. The vigour of international research on immunotherapy for AD provides significant hope for a strong therapeutic lead for the escalating number of individuals who will develop this otherwise incurable condition.


Tg2576 Mouse Cerebral Amyloid Angiopathy Meningoencephalitis Neuropil Thread Amyloid Cascade Hypothesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors are supported by the National Health and Medical Research Council, the Royal Hobart Hospital Research Foundation and the Tasmanian Masonic Medical Research Foundation. The authors have no conflicts of interest that are directly relevant to the content of this article.


  1. 1.
    Vickers JC, Dickson TC, Adlard PA, et al. The cause of neuronal degeneration in Alzheimer’s disease. Prog Neurobiol 2000; 60(2): 139–65PubMedCrossRefGoogle Scholar
  2. 2.
    Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 1991; 82(4): 239–59CrossRefGoogle Scholar
  3. 3.
    Benzing WW, Ikonomovic MD, Brady DR, et al. Evidence that transmitter-containing dystrophic neurites precede paired helical filament and Alz50 formation within senile plaques in the amygdala of nondemented elderly and patients with Alzheimer’s disease. J Comp Neurol 1993; 334(2): 176–91PubMedCrossRefGoogle Scholar
  4. 4.
    Masliah E, Mallory M, Hansen L, et al. An antibody against phosphorylated neurofilaments identifies a subset of damaged association axons in Alzheimer’s disease. Am J Pathol 1993; 142(3): 871–82PubMedGoogle Scholar
  5. 5.
    Su JH, Cummings BJ, Cotman CW. Plaque biogenesis in brain aging and Alzheimer’s disease: I. Progressive changes in states of paired helical filaments and neurofilaments. Brain Res 1996; 739(1–2): 79–87PubMedCrossRefGoogle Scholar
  6. 6.
    Dickson TC, King CE, McCormack GH, et al. Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer’s disease. Exp Neurol 1999; 156(1): 100–10PubMedCrossRefGoogle Scholar
  7. 7.
    Dickson TC, Chuckowree JA, Chuah MI, et al. Novel Alzheimer’s disease pathology reflects variable neuronal vulnerability and demonstrates the role of b-amyloid plaques in neurodegeneration. Neurobiol Dis 2005; 18(2): 286–95PubMedCrossRefGoogle Scholar
  8. 8.
    Braak H, Braak E. Neuropil threads occur in dendrites of tanglebearing nerve cells. Neuropathol Appl Neurobiol 1988; 14(1): 39–44PubMedCrossRefGoogle Scholar
  9. 9.
    Arriagada PV, Growdon JH, Hedley-Whyte ET, et al. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 1992; 42 (3 Pt 1): 631–9PubMedCrossRefGoogle Scholar
  10. 10.
    Lue LF, Brachova L, Civin WH, et al. Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer’s disease neurodegeneration. J Neuropathol Exp Neurol 1996; 55(10): 1083–8PubMedGoogle Scholar
  11. 11.
    Knowles RB, Gomez-Isla T, Hyman BT. Aβ associated neuropil changes: correlation with neuronal loss and dementia. J Neuropathol Exp Neurol 1998; 57(12): 1122–30PubMedCrossRefGoogle Scholar
  12. 12.
    Price JL, Morris JC. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol 1999; 45(3): 358–68PubMedCrossRefGoogle Scholar
  13. 13.
    Loo DT, Copani A, Pike CJ, et al. Apoptosis is induced by βamyloid in cultured central nervous system neurons. Proc Natl Acad Sci U S A 1993; 90(17): 7951–5PubMedCrossRefGoogle Scholar
  14. 14.
    Ivins KJ, Bui ETN, Cotman CW. β-amyloid induces local neurite degeneration in cultured hippocampal neurons: evidence for neuritic apoptosis. Neurobiol Dis 1998; 5(5): 365–78PubMedCrossRefGoogle Scholar
  15. 15.
    Lambert MP, Barlow AK, Chromy BA, et al. Diffusible, nonfibrillar ligands derived from Aβl–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 1998; 95(11): 6448–53PubMedCrossRefGoogle Scholar
  16. 16.
    Wang SS-S, Becerra-Arteaga A, Good TA. Development of a novel diffusion-based method to estimate the size of the aggregated Aβ species responsible for neurotoxicity. Biotechnol Bioeng 2002; 80(1): 50–9PubMedCrossRefGoogle Scholar
  17. 17.
    Sola S, Castro RE, Laires PA, et al. Tauroursodeoxycholic acid prevents amyloid-β peptide-induced neuronal death via a phosphatidylinositol 3-kinase-dependent signaling pathway. Mol Med 2003; 9(9–12): 226–34PubMedGoogle Scholar
  18. 18.
    Caraci F, Chisari M, Frasca G, et al. Nicergoline, a drug used for age-dependent cognitive impairment, protects cultured neurons against β-amyloid toxicity. Brain Res 2005; 1047(1): 30–7PubMedCrossRefGoogle Scholar
  19. 19.
    Estus S, Tucker HM, Van Rooyen C, et al. Aggregated amyloidβ protein induces cortical neuronal apoptosis and concomitant “apoptotic” pattern of gene induction. J Neurosci 1997; 17(20): 7736–45PubMedGoogle Scholar
  20. 20.
    Hartley DM, Walsh DM, Ye CP, et al. Protofibrillar intermediates of amyloid β-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 1999; 19(20): 8876–84PubMedGoogle Scholar
  21. 21.
    Vickers JC, Chin D, Edwards A-M, et al. Dystrophic neurite formation associated with age-related β amyloid deposition in the neocortex: clues to the genesis of neurofibrillary pathology. Exp Neurol 1996; 141(1): 1–11PubMedCrossRefGoogle Scholar
  22. 22.
    Metsaars WP, Hauw J-J, Van Weisem ME, et al. A grading system of Alzheimer disease lesions in neocortical areas. Neurobiol Aging 2003; 24(4): 563–72PubMedCrossRefGoogle Scholar
  23. 23.
    Haass C, Selkoe DJ. Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 1993; 75(6): 1039–42PubMedCrossRefGoogle Scholar
  24. 24.
    Iwatsubo T, Odaka A, Suzuki N, et al. Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ42(43). Neuron 1994; 13(1): 45–53PubMedCrossRefGoogle Scholar
  25. 25.
    Beyreuther K, Masters CL. Alzheimer’s disease: the ins and outs of amyloid-beta. Nature 1997; 389(6652): 677–8PubMedCrossRefGoogle Scholar
  26. 26.
    Hardy J, Duff K, Hardy KG, et al. Genetic dissection of Alzheimer’s disease and related dementias: amyloid and its relationship to tau. Nat Neurosci 1998; 1(5): 355–8PubMedCrossRefGoogle Scholar
  27. 27.
    Selkoe DJ. Amyloid beta-protein and the genetics of Alzheimer’s disease. J Biol Chem 1996; 271(31): 18295–8PubMedGoogle Scholar
  28. 28.
    Sandbrink R, Beyreuther K. Unraveling the molecular pathway of Alzheimer’s disease: research about presenilins gathers momentum. Mol Psychiatry 1996; 1(6): 438–44PubMedGoogle Scholar
  29. 29.
    Bossy-Wetzel E, Schwarzenbacher R, Lipton SA. Molecular pathways to neurodegeneration. Nat Med 2004; 10 Suppl.: S2–9PubMedCrossRefGoogle Scholar
  30. 30.
    Lemere CA, Blusztajn JK, Yamaguchi H, et al. Sequence of deposition of heterogeneous amyloid β-peptides and Apo E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 1996; 3(1): 16–32PubMedCrossRefGoogle Scholar
  31. 31.
    Brion JP. The neurobiology of Alzheimer’s disease. Acta Clinica Belgica 1996; 51(2): 80–90PubMedGoogle Scholar
  32. 32.
    Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F βamyloid precursor protein. Nature 1995; 373(6514): 523–7PubMedCrossRefGoogle Scholar
  33. 33.
    Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 1996; 274(5284): 99–102PubMedCrossRefGoogle Scholar
  34. 34.
    Borchelt DR, Ratovitski T, van Lare J, et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 1997; 19(4): 939–45PubMedCrossRefGoogle Scholar
  35. 35.
    Sturchler-Pierrat C, Abramowski D, Duke M, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 1997; 94(24): 13287–92PubMedCrossRefGoogle Scholar
  36. 36.
    Holcomb L, Gordon MN, McGowan E, et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998; 4(1): 97–100PubMedCrossRefGoogle Scholar
  37. 37.
    Moechars D, Dewachter I, Lorent K, et al. Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem 1999; 274(10): 6483–92PubMedCrossRefGoogle Scholar
  38. 38.
    Janus C, Chishti MA, Westaway D. Transgenic mouse models of Alzheimer’s disease. Biochim Biophys Acta 2000; 1502(1): 63–75PubMedCrossRefGoogle Scholar
  39. 39.
    Mucke L, Masliah E, Yu G-Q, et al. High-level neuronal expression of Aβl–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000; 20(11): 4050–8PubMedGoogle Scholar
  40. 40.
    Chishti MA, Yang D-S, Janus C, et al. Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Bio Chem 2001; 276(24): 21562–70CrossRefGoogle Scholar
  41. 41.
    Blanchard V, Moussaoui S, Czech C, et al. Time sequence of maturation of dystrophic neurites associated with Aβ deposits in APP/PS1 transgenic mice. Exp Neurol 2003; 184(1): 247–63PubMedCrossRefGoogle Scholar
  42. 42.
    Higgins GA, Jacobsen H. Transgenic mouse models of Alzheimer’s disease: phenotype and application. Behav Pharm 2003; 14(5–6): 419–38Google Scholar
  43. 43.
    Richards JG, Higgins GA, Ouagazzal A-M, et al. PS2APP transgenic mice, coexpressing hPS2mut and hAPPswe, show age-related cognitive deficits associated with discrete brain amyloid deposition and inflammation. J Neurosci 2003; 23(26): 8989–9003PubMedGoogle Scholar
  44. 44.
    Cheng IH, Palop JJ, Esposito LA, et al. Aggressive amyloidosis in mice expressing human amyloid peptides with the Arctic mutation. Nat Med 2004; 10(11): 1190–2PubMedCrossRefGoogle Scholar
  45. 45.
    Kawasumi M, Chiba T, Yamada M, et al. Targeted introduction of V642I mutation in amyloid precursor protein gene causes functional abnormality resembling early stage of Alzheimer’s disease in aged mice. Euro J Neurosci 2004; 19(10): 2826–38CrossRefGoogle Scholar
  46. 46.
    Brodaty H, Ames D, Boundy KL, et al. Pharmacological treatment of cognitive deficits in Alzheimer’s disease. Med J Aust 2001; 175(6): 324–7PubMedGoogle Scholar
  47. 47.
    Parnetti L, Senin U, Mecocci P. Cognitive enhancement therapy for Alzheimer’s disease: the way forward. Drugs 1997; 53(5): 752–68PubMedCrossRefGoogle Scholar
  48. 48.
    Lessring MA, Farris W, Chang AY, et al. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 2003; 40(6): 1087–93CrossRefGoogle Scholar
  49. 49.
    Bergamaschini L, Rossi E, Pizzimenti S, et al. Peripheral treatment with enoxaparin, a low molecular weight heparin, reduces plaque and beta-amyloid accumulation in a mouse model of Alzheimer’s disease. J Neurosci 2004; 24(17): 4181–6PubMedCrossRefGoogle Scholar
  50. 50.
    Chauhan NB, Siegel GJ, Feinstein DL. Effects of lovastatin and pravastatin on amyloid processing and inflammatory response in TgCRND8 brain. Neurochem Res 2004; 29(10): 1897–911PubMedCrossRefGoogle Scholar
  51. 51.
    Marr RA, Guan H. Neprilysin regulates amyloid beta peptide levels. J Mol Neurosci 2004; 22(1–2): 5–11PubMedCrossRefGoogle Scholar
  52. 52.
    Arbel M, Yacoby I, Solomon B. Inhibition of amyloid precursor protein processing by β-secretase through site-directed antibodies. Proc Natl Acad Sci U S A 2005; 102(21): 7718–23PubMedCrossRefGoogle Scholar
  53. 53.
    Singer O, Marr RA. Targeting BACE1 siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci 2005; 8(10): 1343–2349PubMedCrossRefGoogle Scholar
  54. 54.
    Asai M, Hattori H, Iwata N, et al. The novel β-secretase inhibitor KMI-429 reduces amyloid β peptide production in amyloid precursor protein transgenic and wild-type mice. J Neurochem 2006; 96(2): 533–40PubMedCrossRefGoogle Scholar
  55. 55.
    McLaurin J, Kierstead ME, Brown ME, et al. Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med 2006; 12(7): 801–8PubMedCrossRefGoogle Scholar
  56. 56.
    Yamada T, Sasaki H, Furuya H, et al. Complementary DNA for the mouse homolog of the human amyloid beta protein precursor. Biochem Biophys Res Commun 1987; 149(2): 665–71PubMedCrossRefGoogle Scholar
  57. 57.
    Check E. Nerve inflammation halts trial for Alzheimer’s drug. Nature 2002; 415(6871): 462PubMedCrossRefGoogle Scholar
  58. 58.
    Orgogozo J-M, Gilman S, Dartigues J-F, et al. Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization. Neurology 2003; 61(1): 46–54PubMedCrossRefGoogle Scholar
  59. 59.
    Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400(6740): 173–7PubMedCrossRefGoogle Scholar
  60. 60.
    Sigurdsson EM, Scholtzova H, Mehta PD, et al. Immunization with a nontoxic/nonfibrillar amyloid-β homologous peptide reduces Alzheimer’s disease associated pathology in transgenic mice. Am J Pathol 2001; 159(2): 439–47PubMedCrossRefGoogle Scholar
  61. 61.
    Bard F, Barbour R, Cannon C, et al. Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer’s disease-like neuropathology. Proc Natl Acad Sci U S A 2003; 100(4): 2023–8PubMedCrossRefGoogle Scholar
  62. 62.
    Das P, Howard V, Loosbrock N, et al. Amyloid-β immunization effectively reduces amyloid deposition in FcRg−/− knock-out mice. J Neurosci 2003; 23(24): 8532–8PubMedGoogle Scholar
  63. 63.
    Lemere CA, Spooner ET, LaFrancois J, et al. Evidence for peripheral clearance of cerebral Aβ protein following chronic, active Aβ immunization in PSAPP mice. Neurobiol Dis 2003; 14(1): 10–8PubMedCrossRefGoogle Scholar
  64. 64.
    Zhang J, Wu X, Qin C, et al. A novel recombinant adenoassociated virus vaccine reduces behavioural impairment and β-amyloid plaques in a mouse model of Alzheimer’s disease. Neurobiol Dis 2003; 14(3): 365–79PubMedCrossRefGoogle Scholar
  65. 65.
    Hara H, Monsonego A, Yuasa K, et al. Development of a safe oral Aβ vaccine using recombinant adeno-associated virus vector for Alzheimer’s disease. J Alzheimers Dis 2004; 6(5): 483–8PubMedGoogle Scholar
  66. 66.
    Kim H-D, Kong F-K, Cao Y, et al. Immunization of Alzheimer model mice with adenovirus vectors encoding amyloid βprotein and GM-CSF reduces amyloid load in the brain. Neurosci Lett 2004; 370(203): 218–23PubMedCrossRefGoogle Scholar
  67. 67.
    Schiltz JG, Salzer U, Mohajeri MH, et al. Antibodies form a DNA peptide vaccination decrease the brain amyloid burden in a mouse model of Alzheimer’s disease. J Mol Med 2004; 82(10): 706–14PubMedCrossRefGoogle Scholar
  68. 68.
    Bowers WJ, Mastrangelo MA, Stanley HA, et al. HSV amplicon-mediated Aβ vaccination in Tg2576 mice: differential antigen-specific immune responses. Neurobiol Aging 2005; 26(4): 393–407PubMedCrossRefGoogle Scholar
  69. 69.
    Buttini M, Masliah E, Barbour R, et al. β-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer’s disease. J Neurosci 2005; 25(40): 9096–101PubMedCrossRefGoogle Scholar
  70. 70.
    Frenkel D, Maron R, Burt DS, et al. Nasal vaccination with a proteasome-based adjuvant and glatiramer acetate clears βamyloid in a mouse model of Alzheimer disease. J Clin Invest 2005; 115(9): 2423–33PubMedCrossRefGoogle Scholar
  71. 71.
    Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer’s disease. Nat Med 2000; 6(8): 916–9PubMedCrossRefGoogle Scholar
  72. 72.
    Bacskai BJ, Kajdasz ST, McLellan ME, et al. Non-Fc-mediated mechanisms are involved in clearance of amyloid-β in vivo by immunotherapy. J Neurosci 2002; 22(18): 7873–8PubMedGoogle Scholar
  73. 73.
    Chauhan NB, Siegel GJ. Intracerebroventricular passive immunization with anti-Abeta antibody in Tg2576. J Neurosci Res 2003; 74(1): 353–7CrossRefGoogle Scholar
  74. 74.
    Lombardo JA, Sterns EA, McLellan ME, et al. Amyloid-β antibody treatment leads to rapid normalization of plaqueinduced neuritic alterations. J Neurosci 2003; 23(34): 10879–83PubMedGoogle Scholar
  75. 75.
    Wilcock DM, DiCarlo G, Henderson D, et al. Intracranially administered anti-Aβ antibodies reduce β-amyloid deposition by mechanisms both independent of and associated with microglial activation. J Neurosci 2003; 23(9): 3745–51PubMedGoogle Scholar
  76. 76.
    Bussière T, Bard F, Barbour B, et al. Morphological characterization of thioflavin-S-positive amyloid plaques in transgenic Alzheimer mice and effect of passive Abeta immunotherapy on their clearance. Am J Pathol 2004; 165(3): 987–95PubMedCrossRefGoogle Scholar
  77. 77.
    Horikoshi Y, Mori T, Maeda M, et al. Aβ N-terminal-end specific antibody reduced β-amyloid in Alzheimer-model mice. Biochem Biophys Res Commun 2004; 325(2): 384–7PubMedCrossRefGoogle Scholar
  78. 78.
    Oddo S, Billings L, Kesslak JP, et al. Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 2004; 43(3): 321–32PubMedCrossRefGoogle Scholar
  79. 79.
    Wilcock DM, Rojiani A, Rosenthal A, et al. Passive immunotherapy against Aβ in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation 2004; 1(1): 24PubMedCrossRefGoogle Scholar
  80. 80.
    Brendza RP, Bacskai BJ, Cirrito JR, et al. Anti-Aβ antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. J Clin Invest 2005; 115(2): 428–33PubMedGoogle Scholar
  81. 81.
    Chauhan NB, Siegel GJ. Efficacy of anti-Aβ antibody isotypes used for intracerebroventricular immunization in TgCRND8. Neurosci Letters 2005; 375(3): 143–7CrossRefGoogle Scholar
  82. 82.
    Hartman RE, Izumi Y, Bales KR, et al. Treatment with an amyloid-β antibody ameliorates plaque load, learning deficits, and hippocampal long-term potentiation in a mouse model of Alzheimer’s disease. J Neurosci 2005; 25(26): 6213–20PubMedCrossRefGoogle Scholar
  83. 83.
    Yamamoto N, Yokoseki T, Shibata M, et al. Suppression of Aβ deposition in brain by peripheral administration of Fab fragments of anti-seed antibody. Biochem Biophys Res Commun 2005; 335(1): 45–7PubMedCrossRefGoogle Scholar
  84. 84.
    Levites Y, Pritam D, Price RW, et al. Anti-Aβ42- and anti-Aβ40-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model. J Clin Invest 2006; 116(1): 193–201PubMedCrossRefGoogle Scholar
  85. 85.
    Lemere CA, Beierschmitt A, Iglesias M, et al. Alzheimer’s disease Aβ vaccine reduces central nervous system Aβ levels in a non-human primate, the Caribbean vervet. Am J Pathol 2004; 165(1): 283–97PubMedCrossRefGoogle Scholar
  86. 86.
    Li S-B, Wang H-Q, Lin X, et al. Specific humoral immune responses in rhesus monkeys vaccinated with the Alzheimer’s disease-associated β-amyloid 1–15 peptide vaccine. 2005; 118(8): 660–4Google Scholar
  87. 87.
    Duff K, Eckman C, Zehr C, et al. Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1. Nature 1996; 383: 710–3PubMedCrossRefGoogle Scholar
  88. 88.
    Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 2003; 39(3): 409–21PubMedCrossRefGoogle Scholar
  89. 89.
    Morgan D, Diamond DM, Gottschall PE, et al. Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 2001; 408(6815): 982–5CrossRefGoogle Scholar
  90. 90.
    Kotilinek LA, Bacskai B, Westerman M, et al. Reversible memory loss in a mouse transgenic model of Alzheimer’s disease. J Neurosci 2002; 22(15): 6331–5PubMedGoogle Scholar
  91. 91.
    Billings LM, Oddo S, Green KN, et al. Intraneuronal Aβ causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 2005; 45(5): 675–88PubMedCrossRefGoogle Scholar
  92. 92.
    Lee EB, Leng LZ, Zhang B, et al. Targeting Aβ oligomers by passive immunization with a conformation selective monoclonal antibody improves learning and memory in APP transgenic mice. J Bio Chem 2006; 281(7): 4292–9CrossRefGoogle Scholar
  93. 93.
    Wilcock DM, Munireddy SK, Rosenthal A, et al. Microglial activation facilitates Aβ plaque removal following intracranial anti-Aβ antibody administration. Neurobiol Dis 2004; 15(1): 11–20PubMedCrossRefGoogle Scholar
  94. 94.
    Dodart JC, Bales KR, Gannon KS, et al. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci 2002; 5(5): 452–7PubMedGoogle Scholar
  95. 95.
    Jensen MT, Mottin MD, Cracchiolo JR, et al. Lifelong immunization with human β-amyloid (1–42) protects Alzheimer’s transgenic mice against cognitive impairment throughout aging. Neurosci 2005; 130(3): 667–84CrossRefGoogle Scholar
  96. 96.
    Klyubin I, Walsh DM, Lemere CA, et al. Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo. Nature Med 2005; 11(5): 556–61PubMedCrossRefGoogle Scholar
  97. 97.
    Spooner ET, Desai RV, Mori C, et al. The generation and characterization of potentially therapeutic Abeta antibodies in mice: differences according to strain and immunization protocol. Vaccine 2002; 21(3–4): 290–7PubMedCrossRefGoogle Scholar
  98. 98.
    Locksley RM, Heinzel FP, Sadik MD, et al. Murine cutaneous leishmaniasis: susceptibility correlates with differential expansion of helper T-cell subsets. Ann Inst Pasteur Immunol 1987; 138(5): 744–9PubMedCrossRefGoogle Scholar
  99. 99.
    Koller MF, Mohajeri MH, Huber M, et al. Active immunization of mice with an Aβ-Hsp70 vaccine. Neurodegener Dis 2003; 1(1): 20–8CrossRefGoogle Scholar
  100. 100.
    Kutzler MA, Cao C, Bai Y, et al. Mapping of immune response following wild-type and mutant Abeta42 plasmid or peptide vaccination in different mouse haplotypes and HLA class II transgenic mice. Vaccine 2006; 24(21): 4630–9PubMedCrossRefGoogle Scholar
  101. 101.
    Monsonego A, Imitola J, Petrovic S, et al. Abeta-induced meningoencephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer’s disease. PNAS 2006; 103(13): 5048–53PubMedCrossRefGoogle Scholar
  102. 102.
    Senior K. Dosing in phase II trial of Alzheimer’s vaccine suspended. Lancet Neurol 2002; 1(1): 3PubMedCrossRefGoogle Scholar
  103. 103.
    Bayer AJ, Bullock R, Jones RW, et al. Evaluation of the safety and immunogenicity of synthetic Aβ42 (AN1792) in patients with AD. Neurology 2005; 64(1): 94–101PubMedCrossRefGoogle Scholar
  104. 104.
    Gilman S, Koller M, Black RS, et al. Clinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005; 64(9): 1553–62PubMedCrossRefGoogle Scholar
  105. 105.
    Lee M, Bard F, Johnson-Wood K, et al. Aβ42 immunization in Alzheimer’s disease generates Aβ N-terminal antibodies. Ann Neurol 2005; 58(3): 430–5PubMedCrossRefGoogle Scholar
  106. 106.
    Nicoll JAR, Wilkinson D, Holmes C, et al. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nat Med 2003; 9(4): 448–52PubMedCrossRefGoogle Scholar
  107. 107.
    Ferrer I, Rovira MB, Sanchez Guerra ML, et al. Neuropathology and pathogenesis of encephalitis following amyloid-β immunization in Alzheimer’s disease. Brain Pathol 2004; 14(1): 11–20PubMedCrossRefGoogle Scholar
  108. 108.
    Masliah E, Hansen L, Adams A, et al. Aβ vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer’s disease. Neurology 2005; 64(1): 129–31PubMedCrossRefGoogle Scholar
  109. 109.
    Lee EB, Leng LZ, Lee VM-Y, et al. Meningoencephalitis associated with passive immunization of a transgenic murine model of Alzheimer’s amyloidosis. FEBS Letters 2005; 579(12): 2564–8PubMedCrossRefGoogle Scholar
  110. 110.
    Racke MM, Boone LI, Hepburn DL, et al. Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid β. Neurobiol Dis 2005; 25(3): 629–36Google Scholar
  111. 111.
    Herber DL, Roth LM, Wilson D, et al. Time-dependent reduction in Aβ levels after intracranial LPS administration in APP transgenic mice. Exp Neurol 2004; 190(1): 245–53PubMedCrossRefGoogle Scholar
  112. 112.
    Carty NC, Wilcock D, Rosenthal A, et al. Intracranial administration of deglycosylated C-terminal-specific anti-Aβ antibody efficiently clears amyloid plaques without activating microglia in amyloid-depositing transgenic mice. J Neuroinflammation 2006; 10(3): 1–11Google Scholar
  113. 113.
    Morgan D. Modulation of microglial activation state following passive immunization in amyloid depositing transgenic mice. Neurochem Int 2006; 49(2): 190–4PubMedCrossRefGoogle Scholar
  114. 114.
    DeMattos RB, Bales KR, Cummins DJ, et al. 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 U S A 2001; 98(15): 8850–5PubMedCrossRefGoogle Scholar
  115. 115.
    DeMattos RB, Bales KR, Parsadanian M, et al. Plaque-associated disruption of CSF and plasma amyloid-beta (Abeta) equilibrium in a mouse model of Alzheimer’s disease. J Neurochem 2002; 81(2): 229–36PubMedCrossRefGoogle Scholar
  116. 116.
    Banks WA, Terrell B, Farr SA, et al. Passage of amyloid beta protein antibody across the blood-brain barrier in a mouse model of Alzheimer’s disease. Peptides 2002; 23(12): 2223–6PubMedCrossRefGoogle Scholar
  117. 117.
    Deane R, Sagare A, Hamm K, et al. IgG-assisted age-dependent clearance of Alzheimer’s amyloid β peptide by the blood-brain barrier neonatal Fc receptor. J Neurosci 2005; 25(50): 11495–503PubMedCrossRefGoogle Scholar
  118. 118.
    Qu B, Rosenberg RN, Li L, et al. Gene vaccination to bias the immune response to amyloid-β peptide as therapy for Alzheimer disease. Arch Neurol 2004; 61(12): 1859–64PubMedCrossRefGoogle Scholar
  119. 119.
    He Y, Sun S-H, Chen RW, et al. Effects of epitopes combination and adjuvants on immune responses to anti-Alzheimer disease DNA vaccines in mice. Alzheimer Dis Assoc Disord 2005; 19(4): 171–7PubMedCrossRefGoogle Scholar
  120. 120.
    Maier M, Seabrook TJ, Lazo ND, et al. 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 2006; 26(18): 4717–28PubMedCrossRefGoogle Scholar
  121. 121.
    Okura Y, Miyakoshi A, Kohyama K, et al. Nonviral Aβ DNA vaccine therapy against Alzheimer’s disease: long-term effects and safety. Proc Natl Acad Sci U S A 2006; 103(25): 9619–24PubMedCrossRefGoogle Scholar
  122. 122.
    Zurbriggen R, Amacker M, Kammer AR, et al. Virosome-based active immunization targets soluble amyloid species rather than plaques in a transgenic mouse model of Alzheimer’s disease. J Mol Neurosci 2005; 27(2): 157–66PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Adele Woodhouse
    • 1
    Email author
  • Tracey C. Dickson
    • 1
  • James C. Vickers
    • 1
  1. 1.School of Medicine, NeuroRepair GroupUniversity of TasmaniaHobartAustralia

Personalised recommendations