The Rationale for an Immunological Approach to Alzheimer's Therapeutics

  • Dave Morgan

Immunotherapy toward the Aβ peptide offers a unique therapeutic approach to the treatment of Alzheimer’s disease. The rationale is that antibodies interacting with the Aβ peptide will accelerate its clearance from the CNS, lead to less amyloid deposition, and reduce the other pathological features of Alzheimer’s disease. Evidence from transgenic mouse models of amyloid deposition is highly supportive of both pathological and functional benefits of this approach. Data from human trials of active immunization (using a vaccine to stimulate generation of antibodies) led to several apparent cases of autoimmune CNS inflammation.


Tg2576 Mouse Amyloid Deposition Amyloid Beta Passive Immunization Amyloid Beta Protein 
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  1. Banks, W. A., Terrell, B., Farr, S. A., Robinson, S. M., Nonaka, N., Morley, J. E. (2002). Passage of amyloid beta protein antibody across the blood–brain barrier in a mouse model of Alzheimer's disease. Peptides, 23, 2223–2226.CrossRefPubMedGoogle Scholar
  2. Bard, F., Cannon, C., Barbour, R., Burke, R. L., Games, D., Grajeda, H., et al. (2000). Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Medicine, 6, 916–919.CrossRefPubMedGoogle Scholar
  3. Carty, N. C., Wilcock, D. M., Rosenthal, A., Grimm, J., Pons, J., Ronan, V., et al. (2006). Intracranial administration of deglycosylated C-terminal-specific anti-Abeta antibody efficiently clears amyloid plaques without activating microglia in amyloid-depositing transgenic mice. Journal of Neuroinflammation, 3, 11.CrossRefPubMedGoogle Scholar
  4. Deane, R., Sagare, A., Hamm, K., Parisi, M., LaRue, B., Guo, H., et al. (2005). IgG-assisted age-dependent clearance of Alzheimer's amyloid beta peptide by the blood–brain barrier neonatal Fc receptor. Journal of Neuroscience, 25, 11495–11503.CrossRefPubMedGoogle Scholar
  5. DeMattos, R. B., Bales, K. R., Parsadanian, M., O'dell, M. A., Foss, E. M., Paul, S. M., et al. (2002). Plaque-associated disruption of CSF and plasma amyloid-beta (Abeta) equilibrium in a mouse model of Alzheimer's disease. Journal of Neurochemistry, 81, 229–236.CrossRefPubMedGoogle Scholar
  6. Dodart, J. C., Bales, K. R., Gannon, K. S., Greene, S. J., DeMattos, R. B., Mathis, C., et al. (2002). Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nature Neuroscience, 5, 452–457.PubMedGoogle Scholar
  7. Ferrer, I., Boada, R. M., Sanchez Guerra, M. L., Rey, M. J., & Costa-Jussa, F. (2004). Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathology, 14, 11–20.PubMedCrossRefGoogle Scholar
  8. Gilman, S., Koller, M., Black, R. S., Jenkins, L., Griffith, S. G., Fox, N. C., et al. (2005). Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64, 1553–1562.CrossRefPubMedGoogle Scholar
  9. Hardy, J. & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science, 297, 353–356.CrossRefPubMedGoogle Scholar
  10. Hock, C., Konietzko, U., Streffer, J. R., Tracy, J., Signorell, A., Muller-Tillmanns, B., et al. (2003). Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron, 38, 547–554.CrossRefPubMedGoogle Scholar
  11. Joseph, J. A., Shukhitt-Hale, B. D. N. A., Martin, A., Perry, G., & Smith, M. A. (2001). Copernicus revisited: Amyloid beta in Alzheimer's disease. Neurobiology of Aging, 22, 131–146.CrossRefPubMedGoogle Scholar
  12. Klyubin, I., Walsh, D. M., Lemere, C. A., Cullen, W. K., Shankar, G. M., Betts, V., et al. (2005). Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo. Nature Medicine, 11, 556–561.CrossRefPubMedGoogle Scholar
  13. Kotilinek, L. A., Bacskai, B., Westerman, M., Kawarabayashi, T., Younkin, L., Hyman, B. T., et al. (2002). Reversible memory loss in a mouse transgenic model of Alzheimer's disease. Journal of Neuroscience, 22, 6331–6335.PubMedGoogle Scholar
  14. Lesne, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., et al. (2006). A specific amyloid-beta protein assembly in the brain impairs memory. Nature, 440, 352–357.CrossRefPubMedGoogle Scholar
  15. Li, Q., Cao, C., Chackerian, B., Schiller, J., Gordon, M., Ugen, K. E., et al. (2004). Overcoming antigen masking of anti-Abeta antibodies reveals breaking of B cell tolerance by virus-like particles in Abeta immunized amyloid precursor protein transgenic mice. BMC Neuroscience, 5, 21.CrossRefPubMedGoogle Scholar
  16. Masliah, E., Hansen, L., Adame, A., Crews, L., Bard, F., Lee, C., et al. (2005). Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology, 64, 129–131.PubMedGoogle Scholar
  17. Morgan, D., Diamond, D. M., Gottschall, P. E., Ugen, K. E., Dickey, C., Hardy, J., et al. (2000). A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature, 408, 982–985.CrossRefPubMedGoogle Scholar
  18. Morgan, D., Gordon, M. N., Tan, J., Wilcock, D., & Rojiani, A. M. (2005). Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics. Journal of Neuropathology and Experimental Neurology, 64, 743–753.CrossRefPubMedGoogle Scholar
  19. Nicoll, J. A., Wilkinson, D., Holmes, C., Steart, P., Markham, H., & Weller, R. O. (2003). Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: A case report. Nature Medicine, 9, 448–452.CrossRefPubMedGoogle Scholar
  20. Orgogozo, J. M., Gilman, S., Dartigues, J. F., Laurent, B., Puel, M., Kirby, L. C., et al. (2003). Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology, 61, 46–54.PubMedGoogle Scholar
  21. Pfeifer, M., Boncristiano, S., Bondolfi, L., Stalder, A., Deller, T., Staufenbiel, M., et al. (2002). Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science, 298, 1379.CrossRefPubMedGoogle Scholar
  22. Racke, M. M., Boone, L. I., Hepburn, D. L., Parsadainian, M., Bryan, M. T., Ness, D. K., et al. (2005). 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 beta. Journal of Neuroscience, 25, 629–636.CrossRefPubMedGoogle Scholar
  23. Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., et al. (1999). Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 400, 173–177.CrossRefPubMedGoogle Scholar
  24. Solomon, B., Koppel, R., Frankel, D., & Hanan-Aharon, E. (1997). Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proceedings of the National Academy of Sciences of the United States of America, 94, 4109–4112.CrossRefPubMedGoogle Scholar
  25. Solomon, B., Koppel, R., Hanan, E., & Katzav, T. (1996). Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proceedings of the National Academy of Sciences of the United States of America, 93, 452–455.CrossRefPubMedGoogle Scholar
  26. Takeuchi, A., Irizarry, M. C., Duff, K., Saido, T. C., Hsiao, A. K., Hasegawa, M., et al. (2000). Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss. The American Journal of Pathology, 157, 331–339.PubMedGoogle Scholar
  27. Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., et al. (2002). Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature, 416, 535–539.CrossRefPubMedGoogle Scholar
  28. Westerman, M. A., Cooper-Blacketer, D., Mariash, A., Kotilinek, L., Kawarabayashi, T., Younkin, L. H., et al. (2002). The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease. Journal of Neuroscience, 22, 1858–1867.PubMedGoogle Scholar
  29. Wilcock, D. M., Alamed, J., Gottschall, P. E., Grimm, J., Rosenthal, A., Pons, J., et al. (2006). Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice. Journal of Neuroscience, 26, 5340–5346.CrossRefPubMedGoogle Scholar
  30. Wilcock, D. M., DiCarlo, G., Henderson, D., Jackson, J., Clarke, K., Ugen, K. E., et al. (2003). Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation. Journal of Neuroscience, 23, 3745–3751.PubMedGoogle Scholar
  31. Wilcock, D. M., Munireddy, S. K., Rosenthal, A., Ugen, K. E., Gordon, M. N., & Morgan, D. (2004). Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. Neurobiology of Disease, 15, 11–20.CrossRefPubMedGoogle Scholar
  32. Wilcock, D. M., Rojiani, A., Rosenthal, A., Levkowitz, G., Subbarao, S., Alamed, J., et al. (2004). Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. Journal of Neuroscience, 24, 6144–6151.CrossRefPubMedGoogle Scholar
  33. Wilcock, D. M., Rojiani, A., Rosenthal, A., Subbarao, S., Freeman, M. J., Gordon, M. N., et al. (2004). Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. Journal of Neuroinflammation, 1, 24.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Dave Morgan
    • 1
  1. 1.Department of Molecular Pharmacology and PhysiologyUniversity of South FloridaTampaUSA

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