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Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model

Nature Neuroscience volume 5, pages 452–457 (2002)Cite this article

Abstract

We have previously shown that chronic treatment with the monoclonal antibody m266, which is specific for amyloid β-peptide (Aβ), increases plasma concentrations of Aβ and reduces Aβ burden in the PDAPP transgenic mouse model of Alzheimer's disease (AD). We now report that administration of m266 to PDAPP mice can rapidly reverse memory deficits in both an object recognition task and a holeboard learning and memory task, but without altering brain Aβ burden. We also found that an Aβ/antibody complex was present in both the plasma and the cerebrospinal fluid of m266-treated mice. Our data indicate that passive immunization with this anti-Aβ monoclonal antibody can very rapidly reverse memory impairment in certain learning and memory tasks in the PDAPP mouse model of AD, owing perhaps to enhanced peripheral clearance and (or) sequestration of a soluble brain Aβ species.

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Figure 1: Passive immunization reversed object recognition memory deficits, but did not reduce Aβ burden, in PDAPP mice.
Figure 2: Object recognition memory performance improved after acute administration of m266 antibody.
Figure 3: Deficits in a holeboard learning task improved after acute administration of m266 antibody.
Figure 4: Dose-dependent effect of m266 on object recognition performance, Aβ plasma levels and m266/Aβ complex formation.

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Acknowledgements

The authors thank R. Gerlai, B. Gitter and P. May for comments on the manuscript and P. Edmonds for editorial assistance.

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Authors and Affiliations

  1. Neuroscience Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, 46285, Indiana, USA

    Jean-Cosme Dodart, Kelly R. Bales, Kimberley S. Gannon, Stephen J. Greene, Cynthia A. DeLong, Su Wu, Xin Wu & Steven M. Paul

  2. Department of Neurology, Center for the Study of Nervous System Injury, Alzheimer's Disease Research Center, Molecular Biology and Pharmacology, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8111, St. Louis, 63110, Missouri, USA

    Ronald B. DeMattos & David M. Holtzman

  3. CNRS UMR 7521, Université Louis Pasteur, 12 rue Goethe, Strasbourg, 67000, France

    Chantal Mathis

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  1. Jean-Cosme Dodart
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Correspondence to Steven M. Paul.

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Competing interests

Eight of the authors are employees of Eli Lilly and Company and therefore have a potential financial interest in the work being reported. Several of the authors are listed on patent applications related to the work. Funding of the project came from Eli Lilly and Company. C.M. has no competing financial interests.

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Dodart, JC., Bales, K., Gannon, K. et al. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model. Nat Neurosci 5, 452–457 (2002). https://doi.org/10.1038/nn842

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