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J. Biol. Chem., Vol. 282, Issue 15, 11436-11445, April 13, 2007

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Conformation-sensitive Antibodies against Alzheimer Amyloid- by Immunization with a Thioredoxin-constrained B-cell Epitope Peptide^*

Nadia Moretto, Angelo Bolchi, Claudio Rivetti, Bruno P. Imbimbo, Gino Villetti, Vladimiro Pietrini^¶, Luciano Polonelli^||, Steven Del Signore^**, Karen M. Smith^**, Robert J. Ferrante^**, and Simone Ottonello¹

From the Department of Biochemistry and Molecular Biology, Chiesi Farmaceutici, R & D Department, ^¶Department of Neurosciences, Neurology Section, and ^||Department of Pathology and Laboratory Medicine, University of Parma, 43100 Parma, Italy, ^**Geriatric Research Education and Clinical Center, Bedford Veterans Affairs Medical Center, Department of Veterans Affairs, Bedford, Massachusetts 01730, and Departments of Neurology, Pathology, and Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118

Immunotherapy against the amyloid- (A) peptide is a valuable potential treatment for Alzheimer disease (AD). An ideal antigen should be soluble and nontoxic, avoid the C-terminally located T-cell epitope of A, and yet be capable of eliciting antibodies that recognize A fibrils and neurotoxic A oligomers but not the physiological monomeric species of A. We have described here the construction and immunological characterization of a recombinant antigen with these features obtained by tandem multimerization of the immunodominant B-cell epitope peptide A1-15 (A15) within the active site loop of bacterial thioredoxin (Trx). Chimeric Trx(A15)_n polypeptides bearing one, four, or eight copies of A15 were constructed and injected into mice in combination with alum, an adjuvant approved for human use. All three polypeptides were found to be immunogenic, yet eliciting antibodies with distinct recognition specificities. The anti-Trx(A15)₄ antibody, in particular, recognized A42 fibrils and oligomers but not monomers and exhibited the same kind of conformational selectivity against transthyretin, an amyloidogenic protein unrelated in sequence to A. We have also demonstrated that anti-Trx(A15)₄, which binds to human AD plaques, markedly reduces A pathology in transgenic AD mice. The data indicate that a conformational epitope shared by oligomers and fibrils can be mimicked by a thioredoxin-constrained A fragment repeat and identify Trx(A15)₄ as a promising new tool for AD immunotherapy.

Received for publication, October 16, 2006 , and in revised form, January 31, 2007.

^* Work carried out in the laboratory of R. J. F. was supported by the NIA, National Institutes of Health Grant AG13846 and the Department of Veterans Affairs. 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 Biochemistry and Molecular Biology, Parco Area delle Scienze 23/A 43100 Parma, Italy. Tel.: 39-0521-905646; Fax: 39-0521-905151; E-mail: s.ottonello{at}unipr.it.

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