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

INTRODUCTION: Our previous studies have shown that amyloid β peptide (Aβ) 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 Aβ antibodies that form immune complexes (ICs) with Aβ, and therefore may be relevant to current Aβ immunotherapy approaches. METHODS: Multidisciplinary methods were employed to demonstrate enhanced complement-mediated capture of Aβ antibody immune complexes compared with Aβ alone in both erythrocytes and THP1-derived macrophages. RESULTS: Aβ antibodies dramatically increased complement activation and opsonization of Aβ, followed by commensurately enhanced Aβ capture by human erythrocytes and macrophages. These in vitro findings were consistent with enhanced peripheral clearance of intravenously administered Aβ antibody immune complexes in nonhuman primates. DISCUSSION: Together with our previous results, showing significant Alzheimer's disease deficits in peripheral Aβ clearance, the present findings strongly suggest that peripheral mechanisms should not be ignored as contributors to the effects of Aβ immunotherapy.