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J. Biol. Chem., Vol. 281, Issue 39, 29268-29277, September 29, 2006

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Neuroserpin Binds A and Is a Neuroprotective Component of Amyloid Plaques in Alzheimer Disease^*

Kerri J. Kinghorn¹², Damian C. Crowther¹³, Lynda K. Sharp, Charlotte Nerelius, Richard L. Davis^¶, Howard T. Chang^¶, Clare Green^||, David C. Gubb^**, Jan Johansson, and David A. Lomas

From the Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 2XY, United Kingdom, the Department of Molecular Biosciences/Medical Biochemistry, Swedish University of Agricultural Sciences, Biomedical Centre, Box 575, S-75123 Uppsala, Sweden, the ^¶Department of Pathology, State University of New York Upstate Medical University, Syracuse, New York 13210, the ^||Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, United Kingdom, and ^**Centro de Investigacion Cooperativa Biogune, Parque Tecnológico de Bizkaia, Edificio 801A, 48160 Derio, Spain

Alzheimer disease is characterized by extracellular plaques composed of A peptides. We show here that these plaques also contain the serine protease inhibitor neuroserpin and that neuroserpin forms a 1:1 binary complex with the N-terminal or middle parts of the A_1-42 peptide. This complex inactivates neuroserpin as an inhibitor of tissue plasminogen activator and blocks the loop-sheet polymerization process that is characteristic of members of the serpin superfamily. In contrast neuroserpin accelerates the aggregation of A_1-42 with the resulting species having an appearance that is distinct from the mature amyloid fibril. Neuroserpin reduces the cytotoxicity of A_1-42 when assessed using standard cell assays, and the interaction has been confirmed in vivo in novel Drosophila models of disease. Taken together, these data show that neuroserpin interacts with A_1-42 to form off-pathway non-toxic oligomers and so protects neurons in Alzheimer disease.

Received for publication, January 24, 2006 , and in revised form, June 21, 2006.

^* This work was supported in part by the Wellcome Trust, Medical Research Council (UK) and Papworth National Health Service Trust. 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 authors contributed equally to this work.

² Has a Merck Sharp and Dohme Limited studentship.

³ To whom correspondence should be addressed: Tel.: 44-1223-764-979; Fax: 44-1223-336-827; E-mail: dcc26{at}cam.ac.uk.

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