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J. Biol. Chem., Vol. 281, Issue 7, 4292-4299, February 17, 2006

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Targeting Amyloid- Peptide (A) Oligomers by Passive Immunization with a Conformation-selective Monoclonal Antibody Improves Learning and Memory in A Precursor Protein (APP) Transgenic Mice^*

Edward B. Lee, Lewis Z. Leng, Bin Zhang, Linda Kwong, John Q. Trojanowski¹, Ted Abel^¶, and Virginia M.-Y. Lee, The John H. Ware III professor of Alzheimer research²

From the Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, the Institute on Aging, University of Pennsylvania School of Medicine, and the ^¶Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Passive immunization of murine models of Alzheimer disease amyloidosis reduces amyloid- peptide (A) levels and improves cognitive function. To specifically address the role of A oligomers in learning and memory, we generated a novel monoclonal antibody, NAB61, that preferentially recognizes a conformational epitope present in dimeric, small oligomeric, and higher order A structures but not full-length amyloid- precursor protein or C-terminal amyloid- precursor protein fragments. NAB61 also recognized a subset of brain A deposits, preferentially mature senile plaques, and amyloid angiopathy. Using NAB61 as immunotherapy, we showed that aged Tg2576 transgenic mice treated with NAB61 displayed significant improvements in spatial learning and memory relative to control mice. These data implicated A oligomers as a pathologic substrate for cognitive decline in Alzheimer disease.

Received for publication, October 11, 2005 , and in revised form, December 5, 2005.

^* This work was supported in part by National Institutes of Health Training Grant T32 AG00255 (to E. B. L.) and NIA, National Institutes of Health Grants AG11542 (to V. M.-Y. L.) and AG008012 (T. A.). 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental table and supplemental methods.

¹ The Measey-Schnabel professor of Geriatric Medicine and Gerontology.

² To whom correspondence should be addressed: Center for Neurodegenerative Disease Research, Dept. of Pathology and Laboratory Medicine, 3rd Fl., Maloney Bldg., 3600 Spruce St., Philadelphia, PA 19104-4283. Tel.: 215-662-6427; Fax: 215-349-5909; E-mail: vmylee{at}mail.med.upenn.edu.

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