Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo (original) (raw)

• Letter
• Published: 17 April 2005
• Dominic M Walsh3,4,
• Cynthia A Lemere3,
• William K Cullen1,2,
• Ganesh M Shankar3,
• Vicki Betts4,
• Edward T Spooner3,
• Liying Jiang3,
• Roger Anwyl1,5,
• Dennis J Selkoe3 &
• …
• Michael J Rowan1,2

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

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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.

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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.).

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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
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2. Dominic M Walsh
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3. Cynthia A Lemere
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4. William K Cullen
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5. Ganesh M Shankar
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6. Vicki Betts
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7. Edward T Spooner
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8. Liying Jiang
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9. Roger Anwyl
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10. Dennis J Selkoe
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11. Michael J Rowan
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Correspondence toDennis J Selkoe or Michael J Rowan.

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

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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

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• Received: 22 October 2004
• Accepted: 09 March 2005
• Published: 17 April 2005
• Issue Date: 01 May 2005
• DOI: https://doi.org/10.1038/nm1234

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