title: Autoantibody-catalyzed hydrolysis of amyloid beta peptide.
abstract: We describe IgM class human autoantibodies that hydrolyze amyloid beta peptide 1-40 (Abeta40). A monoclonal IgM from a patient with Waldenström's macroglobulinemia hydrolyzed Abeta40 at the Lys-28-Gly-29 bond and Lys-16-Ala-17 bonds. The catalytic activity was inhibited stoichiometrically by an electrophilic serine protease inhibitor. Treatment with the catalytic IgM blocked the aggregation and toxicity of Abeta40 in neuronal cell cultures. IgMs purified from the sera of patients with Alzheimer disease (AD) hydrolyzed Abeta40 at rates superior to IgMs from age-matched humans without dementia. IgMs from non-elderly humans expressed the least catalytic activity. The reaction rate was sufficient to afford appreciable degradation at physiological Abeta and IgM concentrations found in peripheral circulation. Increased Abeta concentrations in the AD brain are thought to induce neurodegenerative effects. Peripheral administration of Abeta binding antibodies has been suggested as a potential treatment of AD. Our results suggest that catalytic IgM autoantibodies can help clear Abeta, and they open the possibility of using catalytic Abs for AD immunotherapy.
authors: Chemical Immunology Research Center, Department of Pathology and Laboratory Medicine, University of Texas Houston Medical School, Houston, Texas 77030, USA.
authors: Hiroaki
authors: H
authors: Taguchi
authors: Stephanie
authors: S
authors: Planque
authors: Yasuhiro
authors: Y
authors: Nishiyama
authors: Jindrich
authors: J
authors: Symersky
authors: Stephane
authors: S
authors: Boivin
authors: Paul
authors: P
authors: Szabo
authors: Robert P
authors: RP
authors: Friedland
authors: Paul A
authors: PA
authors: Ramsland
authors: Allen B
authors: AB
authors: Edmundson
authors: Marc E
authors: ME
authors: Weksler
authors: Sudhir
authors: S
authors: Paul
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000276:immunology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000097:blood / Q000737:chemistry* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000737:chemistry* / Q000276:immunology; D001921:Brain / Q000276:immunology / Q000378:metabolism; D002384:Catalysis; D005260:Female; D006801:Humans; D006868:Hydrolysis; D007075:Immunoglobulin M / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D007167:Immunotherapy; D008297:Male; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry; D008258:Waldenstrom Macroglobulinemia / Q000097:blood / Q000276:immunology* / Q000628:therapy
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007075:Immunoglobulin M; D010446:Peptide Fragments; D015842:Serine Proteinase Inhibitors; C078592:amyloid beta-protein (1-40)