Epitope mapping and neuroprotective properties of a human single chain FV antibody that binds an internal epitope of amyloid-beta 1-42

Active and passive immunotherapy targeted at the amyloid-beta (Aβ) peptide has been proposed as therapeutic approach against Alzheimer's disease (AD), and efforts towards the generation and application of antibody-based reagents that are capable of preventing and clearing amyloid aggregates are...

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Bibliographic Details
Published in:Molecular immunology 2008-02, Vol.45 (4), p.881-886
Main Authors: Solórzano-Vargas, R.S., Vasilevko, V., Acero, G., Ugen, K.E., Martinez, R., Govezensky, T., Vazquez-Ramirez, R., Kubli-Garfias, C., Cribbs, D.H., Manoutcharian, K., Gevorkian, G.
Format: Article
Language:English
Subjects:
ADDLs
Alzheimer's disease
Amyloid beta-Peptides - chemistry
Amyloid beta-Peptides - immunology
Amyloid beta-Peptides - pharmacology
Amyloid-beta
Cell Line, Tumor
Cell Survival - drug effects
Complementarity Determining Regions - chemistry
Complementarity Determining Regions - pharmacology
Epitope Mapping
Humans
Immunoglobulin Fragments - chemistry
Immunoglobulin Fragments - pharmacology
Immunoglobulin Heavy Chains - chemistry
Immunoglobulin Heavy Chains - pharmacology
Immunotherapy
Models, Molecular
Neuroprotective Agents - chemistry
Neuroprotective Agents - pharmacology
Neurotoxicity
Oligopeptides - chemistry
Oligopeptides - pharmacology
Peptide Fragments - chemistry
Peptide Fragments - immunology
Peptide Fragments - pharmacology
Protein Binding
Single-chain Fv (scFv) antibodies
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Description
Summary:Active and passive immunotherapy targeted at the amyloid-beta (Aβ) peptide has been proposed as therapeutic approach against Alzheimer's disease (AD), and efforts towards the generation and application of antibody-based reagents that are capable of preventing and clearing amyloid aggregates are currently under active investigation. Previously, we selected and characterized a new anti-Aβ 1-42 phage-displayed scFv antibody, designated clone b4.4, using a non-immune human scFv antibody library and demonstrated that a peptide based on the sequence of the Ig heavy chain (V H) complementarity-determining region (HCDR3) of this antibody fragment bound to Aβ 1-42 and had neuroprotective potential against Aβ 1-42 mediated neurotoxicity in rat hippocampal cultured neurons. In the present study, using novel computational methods and in vitro experiments we demonstrated that b4.4 binds to the central region of Aβ 1-42. We also demonstrated that this scFv antibody binds to Aβ-derived diffusible ligands (ADDLs) and neutralizes the toxicity of both fibrillar and oligomeric forms of Aβ 1-42 tested in vitro in SH-SY5Y cell cultures.
ISSN:0161-5890
1872-9142
DOI:10.1016/j.molimm.2007.08.008