Autoantibody-catalyzed hydrolysis of amyloid beta peptide.
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.
Taguchi
Hiroaki
H
Chemical Immunology Research Center, Department of Pathology and Laboratory Medicine, University of Texas Houston Medical School, Houston, Texas 77030, USA.
Planque
Stephanie
S
Nishiyama
Yasuhiro
Y
Symersky
Jindrich
J
Boivin
Stephane
S
Szabo
Paul
P
Friedland
Robert P
RP
Ramsland
Paul A
PA
Edmundson
Allen B
AB
Weksler
Marc E
ME
Paul
Sudhir
S
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
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)