Conformational Abs recognizing a generic amyloid fibril epitope.
Disease-related amyloid fibrils appear to share a common, but poorly understood, structure. We describe here the generation and preliminary characterization of two conformation-specific mAbs, WO1 and WO2, that bind to the amyloid fibril state of the Alzheimer's peptide A beta(1-40) but not to its soluble, monomeric state. Surprisingly, these Abs also bind to other disease-related amyloid fibrils and amyloid-like aggregates derived from other proteins of unrelated sequence, such as transthyretin, islet amyloid polypeptide, beta(2)-microglobulin, and polyglutamine. At the same time, WO1 and WO2 do not bind to the native protein precursors of these amyloids, nor do they bind to other kinds of protein aggregates. This new class of Abs associated with a fundamental amyloid-folding motif appear to recognize a common conformational epitope with little apparent dependence on amino acid side chain information. These Abs should contribute to the understanding of amyloid structure, assembly, and toxicity and also may benefit the development of diagnostic and therapeutic agents for amyloid diseases.
O'Nuallain
Brian
B
Graduate School of Medicine, University of Tennessee Medical Center, 1924 Alcoa Highway, Knoxville, TN 37920, USA.
Wetzel
Ronald
R
D000682:Amyloid / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal; D001666:Binding Sites, Antibody; D002645:Chickens; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D058228:Islet Amyloid Polypeptide; D008024:Ligands; D009113:Muramidase / Q000276:immunology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology*; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology; D011487:Protein Conformation; D001613:beta 2-Microglobulin / Q000276:immunology
D000682:Amyloid; D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D000939:Epitopes; D058228:Islet Amyloid Polypeptide; D008024:Ligands; D010446:Peptide Fragments; D010455:Peptides; C078592:amyloid beta-protein (1-40); D001613:beta 2-Microglobulin; C097188:polyglutamine; D009113:Muramidase