Peripheral complement interactions with amyloid β peptide in Alzheimer's disease: 2. Relationship to amyloid β immunotherapy

Abstract

Introduction: Our previous studies have shown that amyloid b peptide (Ab) is subject to complement-mediated clearance from the peripheral circulation, and that this mechanism is deficient in Alzheimer's disease. The mechanism should be enhanced by Ab antibodies that form immune complexes (ICs) with Ab, and therefore may be relevant to current Ab immunotherapy approaches. Methods: Multidisciplinary methods were employed to demonstrate enhanced complement-mediated capture of Ab antibody immune complexes compared with Ab alone in both erythrocytes and THP1-derived macrophages. Results: Ab antibodies dramatically increased complement activation and opsonization of Ab, followed by commensurately enhanced Ab capture by human erythrocytes and macrophages. These in vitro findings were consistent with enhanced peripheral clearance of intravenously administered Ab antibody immune complexes in nonhuman primates. Discussion: Together with our previous results, showing significant Alzheimer's disease deficits in peripheral Ab clearance, the present findings strongly suggest that peripheral mechanisms should not be ignored as contributors to the effects of Ab immunotherapy. (C) 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.