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J. Biol. Chem., Vol. 282, Issue 31, 22376-22386, August 3, 2007

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Anti-A_1–11 Antibody Binds to Different -Amyloid Species, Inhibits Fibril Formation, and Disaggregates Preformed Fibrils but Not the Most Toxic Oligomers^*

Grigor Mamikonyan¹, Mihaela Necula¹, Mikayel Mkrtichyan, Anahit Ghochikyan, Irina Petrushina^¶, Nina Movsesyan, Erene Mina, Anatoly Kiyatkin^||, Charles G. Glabe, David H. Cribbs^¶2, and Michael G. Agadjanyan^¶23

From the Department of Immunology, The Institute for Molecular Medicine, Huntington Beach, California 92647, the Department of Molecular Biology and Biochemistry and the ^¶Institute for Brain Aging and Dementia, University of California, Irvine, California 92697, and the ^||Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19115

Different strategies proposed as therapy for Alzheimer disease (AD) have aimed to reduce the level of toxic forms of A peptide in the brain. Here, we directly analyze the therapeutic utility of the polyclonal anti-A_1–11 antibody induced in 3xTg-AD mice vaccinated with the second generation prototype epitope vaccine. Substoichiometric concentrations of purified anti-A_1–11 antibody prevented aggregation of A₄₂ and induced disaggregation of preformed A₄₂ fibrils down to nonfilamentous and nontoxic species. Anti-A_1–11 antibody delayed A₄₂ oligomer formation but ultimately appeared to stabilize nonfibrillar conformations, including oligomer-like assemblies. The reduced oligomer-mediated cytotoxicity observed upon preincubation of A oligomers with the anti-A_1–11 antibody in the absence of oligomer disaggregation suggests a possible oligomer rearrangement in the presence of the antibody. These in vitro observations suggest that preventive vaccination may protect from AD or may delay the onset of the disease, whereas therapeutic vaccination cannot disrupt the toxic oligomers and may only minimally alleviate preexisting AD pathology.

Received for publication, January 4, 2007 , and in revised form, May 31, 2007.

^* This work was supported by National Institutes of Health R01 Grants AG20241 and NS50895 (to D. H. C. and M. G. A.) and NS3I230 (to C. G. C.) and Alzheimer's Association Grant IIRG-03-6279 (to M. G. A. and D. H. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These two authors contributed equally to this work.

² Both senior authors contributed equally to this work.

³ To whom correspondence should be addressed: The Institute for Molecular Medicine, 16371 Gothard St., H, Huntington Beach, CA 92647-3652. Tel.: 714-596-7821; Fax: 714-596-3791; E-mail: magadjanyan{at}immed.org.

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