br Acknowledgments and Disclosures br Introduction Over
Acknowledgments and Disclosures
Introduction Over the last decade, the most visible strategy for the treatment of Alzheimer's disease (AD) has been amyloid β peptide (Aβ) immunotherapy (reviewed in ). Although the first efforts with Aβ immunotherapy failed to complete clinical trials , AD transgenic mice [2,3] and human AD patients [4,5] did show significantly reduced Aβ burden after treatment. Perhaps as a result, Aβ immunization approaches continue to be pursued . A critical, unresolved issue with Aβ immunization is whether or not its presumed mechanism of action, enhanced glial clearance of brain Aβ (e.g., [6–8]), provides a sufficient explanation for its reported effects. For example, an Aβ antibody, m266, that did not react with brain Aβ deposits and appeared to have most if not all of its effect in the periphery, nonetheless reduced brain Aβ levels in a transgenic AD mouse model . This antibody formed immune complexes (ICs) with Aβ in the peripheral circulation  and appeared to induce efflux of brain Aβ to plasma [9,11], leading to the “peripheral sink” hypothesis [9–11]. Moreover, the penetration of Aβ A 779 receptor into the central nervous system (CNS) remains open to debate. Levites et al. , for example, reported that only 1 fmol/mg of Aβ antibody could be detected in AD transgenic mouse brain after a 500-μg intraperitoneal injection. This brain concentration of antibody is nearly three orders of magnitude less than estimates of total brain Aβ in the mice . Cerebrospinal fluid concentrations of bapineuzumab, a humanized monoclonal Aβ antibody, are also found to be, on a molar basis, approximately three orders of magnitude less than typical cerebrospinal fluid Aβ concentrations (reviewed in ). The above considerations, of course, do not necessarily disallow direct CNS actions of Aβ immunotherapeutics. Golde , for example, has cogently argued that if endogenous antibodies can have material effects on the CNS, which is clearly the case [15,16], then exogenous antibodies should be able to do so as well. On the other hand, considering that only minute quantities of peripherally administered Aβ antibodies reach the CNS, whereas they are wholly and directly exposed to circulating Aβ, it is difficult to understand how interactions of Aβ antibodies with circulating Aβ can be ignored as at least a potential, additional mechanism of action for Aβ immunotherapy. We have explored specific mechanisms by which Aβ/Aβ antibody immune complexes (Aβ ICs) formed in blood in the course of Aβ immunization might enhance clearance of Aβ through enhanced interactions with the complement system. These studies were informed by the fact that major pathways for peripheral pathogen clearance in primates hinge on complement receptor 1 (CR1) , single nucleotide polymorphisms in which have been consistently identified as a significant risk factor for AD [18–22]. Compared with Aβ alone, we found that the presence of Aβ antibodies in the fluid phase dramatically increased virtually all steps in the major pathways for peripheral pathogen clearance in primates including complement activation, formation of complement-opsonized complexes that are ligands for CR1, and peripheral capture and disposal of Aβ through CR1-mediated erythrocyte and macrophage mechanisms. Consistent with these in vitro results, clearance of Aβ from plasma and erythrocyte compartments in vivo was also robustly enhanced in nonhuman primates intravenously (IV) inoculated with Aβ ICs. Although, as noted, these findings do not disallow CNS actions of Aβ immunotherapy, they do strongly suggest that peripheral effects should be considered as well—particularly because peripheral strategies might avoid the CNS adverse effects that have been encountered in previous AD immunotherapy trials [1,4,5].