Autoantibody-catalyzed Hydrolysis of Amyloid β Peptide

Hiroaki Taguchi,Stephanie Planque,Yasuhiro Nishiyama,Jindrich Symersky,Stephane Boivin,Paul Szabo,Robert P Friedland,Paul A Ramsland,Allen B Edmundson,Marc E Weksler,Sudhir Paul

doi:10.1074/jbc.m707983200

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.

Highlights

(APP) residues 597– 636) with A␤-(1– 42) (A␤42; APP residues 597– 638) being the next-most abundant product [2]
We reported previously the hydrolysis of amyloid ␤ peptide 1– 40 (A␤40) by the cross-reactive light chain subunit of catalytic Abs to the neuropeptide vasoactive intestinal peptide [13]
In the present study we examined the ability of monoclonal and polyclonal IgM preparations from humans to catalyze the hydrolysis of A␤40

Summary

Introduction

(APP) residues 597– 636) with A␤-(1– 42) (A␤42; APP residues 597– 638) being the next-most abundant product [2]. Intravenous administration of A␤ binding monoclonal antibodies (Abs) of the IgG class to transgenic mice expressing human A␤, which are frequently used as an experimental model of AD, clears amyloid plaques from the brain and improves cognitive performance (a) Small amounts of the IgGs cross the blood-brain barrier (BBB) and bind A␤s in the brain, and microglial cells clear the resultant immune complexes by Fc-receptor mediated uptake [9]; and (b) according to the “peripheral sink” hypothesis [10], A␤s can be cleared from the brain without the requirement for IgG entry into the brain In this hypothesis peripheral A␤-Ab binding perturbs the equilibrium between the peptide pools in the brain and periphery, thereby stimulating A␤ release from the brain. We report the properties of specific A␤-hydrolyzing IgMs in aged humans and AD patients, and we present alternative arguments supporting their beneficial versus deleterious roles

Methods

Results

Conclusion