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Conformation-sensitive antibodies against alzheimer amyloid-beta by immunization with a thioredoxin-constrained B-cell epitope peptide.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2007 Apr 13; Vol. 282 (15), pp. 11436-45. Date of Electronic Publication: 2007 Jan 31. - Publication Year :
- 2007
-
Abstract
- Immunotherapy against the amyloid-beta (Abeta) 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 Abeta, and yet be capable of eliciting antibodies that recognize Abeta fibrils and neurotoxic Abeta oligomers but not the physiological monomeric species of Abeta. 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 Abeta1-15 (Abeta15) within the active site loop of bacterial thioredoxin (Trx). Chimeric Trx(Abeta15)n polypeptides bearing one, four, or eight copies of Abeta15 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(Abeta15)4 antibody, in particular, recognized Abeta42 fibrils and oligomers but not monomers and exhibited the same kind of conformational selectivity against transthyretin, an amyloidogenic protein unrelated in sequence to Abeta. We have also demonstrated that anti-Trx(Abeta15)4, which binds to human AD plaques, markedly reduces Abeta pathology in transgenic AD mice. The data indicate that a conformational epitope shared by oligomers and fibrils can be mimicked by a thioredoxin-constrained Abeta fragment repeat and identify Trx(Abeta15)4 as a promising new tool for AD immunotherapy.
- Subjects :
- Alzheimer Disease metabolism
Alzheimer Disease pathology
Amyloid beta-Peptides chemistry
Amyloid beta-Peptides metabolism
Animals
Brain metabolism
Brain pathology
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Transgenic
Models, Molecular
Protein Structure, Tertiary
Recombinant Proteins chemistry
Recombinant Proteins immunology
Recombinant Proteins metabolism
Thioredoxins chemistry
Thioredoxins metabolism
Alzheimer Disease immunology
Amyloid beta-Peptides immunology
Antibodies immunology
Epitopes, B-Lymphocyte immunology
Peptide Fragments immunology
Thioredoxins immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 282
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 17267402
- Full Text :
- https://doi.org/10.1074/jbc.M609690200