Abstract
Anti-amyloid immunotherapy has been proposed as an appropriate therapeutic approach for Alzheimer's disease (AD). Significant efforts have been made towards the generation and assessment of antibody-based reagents capable of preventing and clearing amyloid aggregates as well as preventing their synaptotoxic effects. In this study, we selected a novel set of human anti-amyloid-beta peptide 1-42 (Abeta1-42) recombinant monoclonal antibodies in a single chain fragment variable (scFv) and a single-domain (VH) format. We demonstrated that these antibody fragments recognize in a specific manner amyloid-beta deposits in APP/Tg mouse brains, inhibit toxicity of oligomeric Abeta1-42 in neuroblastoma cell cultures in a concentration-dependent manner and reduced amyloid deposits in APP/Tg2576 mice after intracranial administration. These antibody fragments recognize epitopes in the middle/C-terminus region of Abeta, which makes them strong therapeutic candidates due to the fact that most of the Abeta species found in the brains of AD patients display extensive N-terminus truncations/modifications.
Copyright 2010 Elsevier B.V. All rights reserved.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Amyloid beta-Peptides / administration & dosage*
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / immunology*
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Animals
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Antibodies, Monoclonal / chemistry*
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Antibodies, Monoclonal / genetics
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Antibodies, Monoclonal / metabolism
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Bacteriophage M13 / chemistry
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Bacteriophage M13 / genetics
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Bacteriophage M13 / immunology*
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Binding Sites, Antibody / genetics
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Cell Line, Tumor
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Epitopes / genetics
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Epitopes / immunology*
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Epitopes / metabolism
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Humans
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Immunoglobulin Heavy Chains / chemistry*
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Immunoglobulin Heavy Chains / genetics
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Immunoglobulin Heavy Chains / metabolism
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Mice
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Mice, Transgenic
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Molecular Sequence Data
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Peptide Fragments / administration & dosage*
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Peptide Fragments / genetics
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Peptide Fragments / immunology*
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Peptide Library*
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Protein Structure, Tertiary / genetics
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Single-Chain Antibodies / biosynthesis
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Single-Chain Antibodies / chemistry*
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Single-Chain Antibodies / genetics
Substances
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Amyloid beta-Peptides
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Antibodies, Monoclonal
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Epitopes
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Immunoglobulin Heavy Chains
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Peptide Fragments
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Peptide Library
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Recombinant Proteins
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Single-Chain Antibodies
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amyloid beta-protein (1-42)