Nature Medicine
11, 556 - 561 (2005)
Published online: 17 April 2005; | doi:10.1038/nm1234
Amyloid  protein immunotherapy neutralizes A oligomers that disrupt synaptic plasticity in vivoIgor Klyubin1, 2, 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, 21
Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland. 2
Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland. 3
Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. 4
Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. 5
Department of Physiology, Trinity College, Dublin 2, Ireland.
Correspondence should be addressed to Dennis J Selkoe dselkoe@rics.bwh.harvard.edu or Michael J Rowan mrowan@tcd.ieOne of the most clinically advanced forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloid  protein (A)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 A could exert a beneficial action by directly neutralizing potentially synaptotoxic soluble A species14,
15,
16 in the brain. Intracerebroventricular injection of naturally secreted human A inhibited long-term potentiation (LTP), a correlate of learning and memory17, in rat hippocampus in vivo but a monoclonal antibody to A completely prevented the inhibition of LTP when injected after A. Size fractionation showed that A oligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an A antibody again prevented such inhibition. Active immunization against A was partially effective, and the effects correlated positively with levels of antibodies to A oligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble A 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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