Autoantibody-catalyzed hydrolysis of amyloid β peptide

We describe IgM class human autoantibodies that hydrolyze amyloid beta peptide 1-40 (A beta 40). A monoclonal IgM from a patient with Waldenstrom's macroglobulinemia hydrolyzed A beta 40 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 A beta 40 in neuronal cell cultures. IgMs purified from the sera of patients with Alzheimer disease (AD) hydrolyzed A beta 40 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 A beta and IgM concentrations found in peripheral circulation. Increased A beta concentrations in the AD brain are thought to induce neurodegenerative effects. Peripheral administration of A beta binding antibodies has been suggested as a potential treatment of AD. Our results suggest that catalytic IgM autoantibodies can help clear A beta, and they open the possibility of using catalytic Abs for AD immunotherapy.