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J. Biol. Chem., Vol. 283, Issue 33, 22550-22556, August 15, 2008

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Antibodies to Potato Virus Y Bind the Amyloid β Peptide

IMMUNOHISTOCHEMICAL AND NMR STUDIES^*

Robert P. Friedland¹, Johnathan M. Tedesco, Andrea C. Wilson^¶, Craig S. Atwood^¶, Mark A. Smith^||, George Perry^**, and Michael G. Zagorski

From the Departments of Neurology, Chemistry, and ^||Pathology, Case Western Reserve University, Cleveland, Ohio 44106, the ^¶Department of Medicine, University of Wisconsin, and the Geriatric Research, Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705, and the ^**University of Texas at San Antonio College of Sciences, San Antonio, Texas 78249

Studies in transgenic mice bearing mutated human Alzheimer disease (AD) genes show that active vaccination with the amyloid β (Aβ) protein or passive immunization with anti-Aβ antibodies has beneficial effects on the development of disease. Although a trial of Aβ vaccination in humans was halted because of autoimmune meningoencephalitis, favorable effects on Aβ deposition in the brain and on behavior were seen. Conflicting results have been observed concerning the relationship of circulating anti-Aβ antibodies and AD. Although these autoantibodies are thought to arise from exposure to Aβ, it is also possible that homologous proteins may induce antibody synthesis. We propose that the long-standing presence of anti-Aβ antibodies or antibodies to immunogens homologous to the Aβ protein may produce protective effects. The amino acid sequence of the potato virus Y (PVY) nuclear inclusion b protein is highly homologous to the immunogenic N-terminal region of Aβ. PVY infects potatoes and related crops worldwide. Here, we show through immunocytochemistry, enzyme-linked immunosorbent assay, and NMR studies that mice inoculated with PVY develop antibodies that bind to Aβ in both neuritic plaques and neurofibrillary tangles, whereas antibodies to material from uninfected potato leaf show only modest levels of background immunoreactivity. NMR data show that the anti-PVY antibody binds to Aβ within the Phe⁴–Ser⁸ and His¹³–Leu¹⁷ regions. Immune responses generated from dietary exposure to proteins homologous to Aβ may induce antibodies that could influence the normal physiological processing of the protein and the development or progression of AD.

Received for publication, March 17, 2008 , and in revised form, May 14, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01-AG017173 and R01-AG027853. This work was also supported by the Fullerton Family, the Joseph and Florence Mandel Research Fund, the Nickman Family, Philip Morris USA, GOJO Corp., and the Institute for the Study of Aging. 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 To whom correspondence should be addressed: Dept. of Neurology, Case Western Reserve University School of Medicine, 10900 Euclid Ave., T504 SOM, Cleveland, OH 44122. Tel.: 216-368-1913; E-mail: robert.friedland{at}case.edu.

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