Epitopes described in "Monoclonal antibodies that target pathological assemblies of Abeta."

Article Authors:Mary P Lambert; Pauline T Velasco; Lei Chang; Kirsten L Viola; Sara Fernandez; Pascale N Lacor; Daliya Khuon; Yuesong Gong; Eileen H Bigio; Pamela Shaw; Fernanda G De Felice; Grant A Krafft; William L Klein
Article Title:Monoclonal antibodies that target pathological assemblies of Abeta.
Reference Detail
Reference ID:1011446
Abstract:Amyloid beta (Abeta) immunotherapy for Alzheimer's disease has shown initial success in mouse models of Alzheimer's disease and in human patients. However, because of meningoencephalitis in clinical trials of active vaccination, approaches using therapeutic antibodies may be preferred. As a novel antigen to generate monoclonal antibodies, the current study has used Abeta oligomers (amyloid beta-derived diffusible ligands, ADDLs), pathological assemblies known to accumulate in Alzheimer's disease brain. Clones were selected for the ability to discriminate Alzheimer's disease from control brains in extracts and tissue sections. These antibodies recognized Abeta oligomers and fibrils but not the physiologically prevalent Abeta monomer. Discrimination derived from an epitope found in assemblies of Abeta1-28 and ADDLs but not in other sequences, including Abeta1-40. Immunoneutralization experiments showed that toxicity and attachment of ADDLs to synapses in culture could be prevented. ADDL-induced reactive oxygen species (ROS) generation was also inhibited, establishing this response to be oligomer-dependent. Inhibition occurred whether ADDLs were prepared in vitro or obtained from Alzheimer's disease brain. As conformationally sensitive monoclonal antibodies that selectively immunoneutralize binding and function of pathological Abeta assemblies, these antibodies provide tools by which pathological Abeta assemblies from Alzheimer's disease brain might be isolated and evaluated, as well as offering a valuable prototype for new antibodies useful for Alzheimer's disease therapeutics.
Affiliations:Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA.
Reference Type:Literature
PubMed ID:17116235
Journal:J Neurochem
Journal Volume:100
Article Pages:23-35
Journal ISSN:1471-4159
Article Chemical List:ADD3 protein, human;Amyloid beta-Peptides;Antibodies, Monoclonal;Calmodulin-Binding Proteins;Epitopes;Glial Fibrillary Acidic Protein;Peptide Fragments;Reactive Oxygen Species;Tetrazolium Salts;Thiazoles;thiazolyl blue
Article MeSH List:Alzheimer Disease(metabolism; pathology); Amyloid beta-Peptides(chemistry; immunology; metabolism); Animals; Antibodies, Monoclonal(physiology); Antibody Specificity; Brain(metabolism; pathology); Calmodulin-Binding Proteins(metabolism); Cells, Cultured; Dose-Response Relationship, Drug; Epitopes; Glial Fibrillary Acidic Protein(metabolism); Humans; Immunoblotting(methods); Immunohistochemistry(methods); Mice; Neurons(metabolism); Peptide Fragments(immunology; pharmacology); Protein Binding(drug effects); Rabbits; Reactive Oxygen Species(metabolism); Tetrazolium Salts(diagnostic use); Thiazoles(diagnostic use)
Curation Last Updated:2014-10-03 21:08:00