Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo

Nature Medicine volume 11, pages 556–561 (2005)Cite this article

Abstract

One of the most clinically advanced forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloid β protein (Aβ)1,2,3,4,5,6,7, but how this may prevent cognitive impairment is unclear8,9,10,11,12,13. We hypothesized that antibodies to Aβ could exert a beneficial action by directly neutralizing potentially synaptotoxic soluble Aβ species14,15,16 in the brain. Intracerebroventricular injection of naturally secreted human Aβ inhibited long-term potentiation (LTP), a correlate of learning and memory17, in rat hippocampus in vivo but a monoclonal antibody to Aβ completely prevented the inhibition of LTP when injected after Aβ. Size fractionation showed that Aβ oligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an Aβ antibody again prevented such inhibition. Active immunization against Aβ was partially effective, and the effects correlated positively with levels of antibodies to Aβ oligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble Aβ oligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: In vivo administration of monoclonal antibodies to Aβ prevents the inhibition of hippocampal LTP by naturally secreted Aβ.
Figure 2: Direct neutralization of naturally secreted Aβ in the brain by antibody to Aβ.
Figure 3: Oligomers are the synaptotoxic Aβ species neutralized by antibodies to Aβ in vivo.
Figure 4: Endogenous antibodies to Aβ partially prevent the inhibition of LTP by natural Aβ oligomers.

Similar content being viewed by others

References

  1. Nicoll, J.A.R. et al. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nat. Med. 9, 448–452 (2003).

    Article  CAS  Google Scholar 

  2. Hock, C. et al. Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease. Neuron 38, 547–554 (2003).

    Article  CAS  Google Scholar 

  3. McGeer, P.L. & McGeer, E. Is there a future for vaccination as a treatment for Alzheimer's disease? Neurobiol. Aging 24, 391–395 (2003).

    Article  CAS  Google Scholar 

  4. Orgogozo, J.M. et al. Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization. Neurology 61, 46–54 (2003).

    Article  CAS  Google Scholar 

  5. Nicoll, J.A.R. et al. Specificity of mechanisms for plaque removal after Aβ immunotherapy for Alzheimer disease – Reply. Nat. Med. 10, 118–119 (2004).

    Article  CAS  Google Scholar 

  6. Schenk, D., Hagen, M. & Seubert, P. Current progress in β-amyloid immunotherapy. Curr. Opin. Immunol. 16, 599–606 (2004).

    Article  CAS  Google Scholar 

  7. Robinson, S., Bishop, G., Lee, H. & Munch, G. Lessons from the AN 1792 Alzheimer vaccine: lest we forget. Neurobiol. Aging, 609–615 (2004).

  8. Bard, F. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916–919 (2000).

    Article  CAS  Google Scholar 

  9. DeMattos, R.B. et al. Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 98, 8850–8855 (2001).

    Article  CAS  Google Scholar 

  10. Bacskai, B.J. et al. Imaging of amyloid-β deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat. Med. 7, 369–372 (2001).

    Article  CAS  Google Scholar 

  11. Dodart, J.C. et al. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model. Nat. Neurosci. 5, 452–457 (2002).

    Article  CAS  Google Scholar 

  12. Kotilinek, L.A. et al. Reversible memory loss in a mouse transgenic model of Alzheimer's disease. J. Neurosci. 22, 6331–6335 (2002).

    Article  CAS  Google Scholar 

  13. Wilcock, D.M. et al. Microglial activation facilitates Aβ plaque removal following intracranial anti-Aβ antibody administration. Neurobiol. Dis. 15, 11–20 (2004).

    Article  CAS  Google Scholar 

  14. Lue, L.F. et al. Soluble amyloid β peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am. J. Pathol. 155, 853–862 (1999).

    Article  CAS  Google Scholar 

  15. McLean, C.A. et al. Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann. Neurol. 46, 860–866 (1999).

    Article  CAS  Google Scholar 

  16. Wang, J., Dickson, D.W., Trojanowski, J.Q. & Lee, V.M. The levels of soluble versus insoluble brain Aβ distinguish Alzheimer's disease from normal and pathologic aging. Exp. Neurol. 158, 328–37 (1999).

    Article  CAS  Google Scholar 

  17. Morris, R.G.M. et al. Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory. Philos. Trans. R. Soc. Lond. B Biol. Sci. 358, 773–786 (2003).

    Article  CAS  Google Scholar 

  18. Walsh, D.M. et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002).

    Article  CAS  Google Scholar 

  19. Kim, K.S. et al. Production and characterization of monoclonal antibodies reactive to synthetic cerebrovascular amyloid peptide. Neurosci. Res. Commun. 2, 121–130 (1988).

    CAS  Google Scholar 

  20. Walsh, D.M., Tseng, B.P., Rydel, R.E., Podlisny, M.B. & Selkoe, D.J. The oligomerization of amyloid β-protein begins intracellularly in cells derived from human brain. Biochemistry 39, 10831–10839 (2000).

    Article  CAS  Google Scholar 

  21. Gong, Y.S. et al. Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc. Natl. Acad. Sci. USA 100, 10417–10422 (2003).

    Article  CAS  Google Scholar 

  22. Wang, Q.W., Walsh, D.M., Rowan, M.J., Selkoe, D.J. & Anwyl, R. Block of long-term potentiation by naturally secreted and synthetic amyloid β-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. J. Neurosci. 24, 3370–3378 (2004).

    Article  CAS  Google Scholar 

  23. Chauhan, M., Siegel, G. & Lichtor, T. Distribution of intraventricularly administered antiamyloid-β peptide (Aβ) antibody in the mouse brain. J. Neurosci. Res. 66, 231–235 (2001).

    Article  CAS  Google Scholar 

  24. Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999).

    Article  CAS  Google Scholar 

  25. Xia, W. et al. Presenilin 1 regulates the processing of β-amyloid precursor protein C-terminal fragments and the generation of amyloid β-protein in endoplasmic reticulum and Golgi. Biochemistry 37, 16465–16471 (1998).

    Article  CAS  Google Scholar 

  26. Walsh, D.M. et al. Certain inhibitors of synthetic Aβ fibrillogenesis block oligomerization of natural Aβ and thereby rescue long term potentiation. J. Neurosci. 25, 2455–2462 (2005).

    Article  CAS  Google Scholar 

  27. Walsh, D.M., Lomakin, A., Benedek, G.B., Condron, M.M. & Teplow, D.B. Amyloid β-protein fibrillogenesis. Detection of a protofibrillar intermediate. J. Biol. Chem. 272, 22364–22372 (1997).

    Article  CAS  Google Scholar 

  28. Walsh, D. et al. Amyloid β-protein fibrillogenesis: structure and biological activity of protofibrillar intermediates. J. Biol. Chem. 274, 25945–25952 (1999).

    Article  CAS  Google Scholar 

  29. Lemere, C., Spooner, E., Leverone, J., Mori, C. & Clements, J. Intranasal immunotherapy for the treatment of Alzheimer's disease: Escherichia coli LT and LT(R192G) as mucosal adjuvants. Neurobiol. Aging 23, 991–1000 (2002).

    Article  CAS  Google Scholar 

  30. Lemere, C. 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. 3, 16–32 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was funded by Science Foundation Ireland (M.R. and R.A.), the Health Research Board of Ireland (M.R. and R.A.), Enterprise Ireland (M.R. and R.A.), the Irish Higher Education Authority (Programme for Research in Third Level Institutions) (M.R. and R.A.), the Wellcome Trust (M.R., R.A. and D.W.), the US National Institutes of Health (grant number AG06173 to D.S.) and the Foundation for Neurologic Diseases (C.L. and D.S.).

Author information

Authors and Affiliations

  1. Trinity College Institute of Neuroscience, Trinity College, Dublin, 2, Ireland

    Igor Klyubin, William K Cullen, Roger Anwyl & Michael J Rowan

  2. Department of Pharmacology and Therapeutics, Trinity College, Dublin, 2, Ireland

    Igor Klyubin, William K Cullen & Michael J Rowan

  3. Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, 02115, Massachusetts, USA

    Dominic M Walsh, Cynthia A Lemere, Ganesh M Shankar, Edward T Spooner, Liying Jiang & Dennis J Selkoe

  4. Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, 4, Ireland

    Dominic M Walsh & Vicki Betts

  5. Department of Physiology, Trinity College, Dublin, 2, Ireland

    Roger Anwyl

Authors
  1. Igor Klyubin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dominic M Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cynthia A Lemere
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William K Cullen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ganesh M Shankar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vicki Betts
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Edward T Spooner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Liying Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Roger Anwyl
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dennis J Selkoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michael J Rowan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Dennis J Selkoe or Michael J Rowan.

Ethics declarations

Competing interests

Dennis J. Selkoe is a consultant to Elan, plc.

Supplementary information

Supplementary Table 1

Isotope analysis (PDF 24 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klyubin, I., Walsh, D., Lemere, C. et al. Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo. Nat Med 11, 556–561 (2005). https://doi.org/10.1038/nm1234

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1234

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing