ABSTRACT
Accumulation of amyloid beta (Abeta) is a pathological hallmark of Alzheimer's disease, and lowering Abeta is a promising therapeutic approach. Intact anti-Abeta antibodies reduce brain Abeta through two pathways: enhanced microglial phagocytosis and Abeta transfer from the brain to the periphery (Abeta sequestration). While activation of microglia, which is essential for microglial phagocytosis, is necessarily accompanied by undesired neuroinflammatory events, the capacity for sequestration does not seem to be linked to such effects. We and other groups have found that simple Abeta binding agents are sufficient to reduce brain Abeta through the sequestration pathway. In this study, we aimed to eliminate potentially deleterious immune activation from antibodies without affecting the ability to induce sequestration. The glycan portion of immunoglobulin is critically involved in interactions with immune effectors including the Fc receptor and complement c1q; deglycosylation eliminates these interactions, while antigen (Abeta)-binding affinity is maintained. In this study, we investigated whether deglycosylated anti-Abeta antibodies reduce microglial phagocytosis and neuroinflammation without altering the capacity to induce Abeta sequestration. Deglycosylated antibodies maintained Abeta binding affinity. Deglycosylated antibodies did not enhance Abeta phagocytosis or cytokine release in primary cultured microglia, whereas intact antibodies did so significantly. Intravenous injection of deglycosylated antibodies elevated plasma Abeta levels and induced Abeta sequestration to a similar or greater degree compared with intact antibodies in an Alzheimer's transgenic mouse model without or with Abeta plaque pathology. We conclude that deglycosylated antibodies effectively induced Abeta sequestration without provoking neuroinflammation; thus, these deglycosylated antibodies may be optimal for sequestration therapy for Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/antagonists & inhibitors , Antibodies/pharmacology , Cytokines/drug effects , Microglia/drug effects , Phagocytosis/drug effects , Alzheimer Disease/immunology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/chemical synthesis , Amyloid beta-Peptides/immunology , Animals , Animals, Newborn , Antibodies/immunology , Antibodies/therapeutic use , Brain/drug effects , Brain/immunology , Brain/metabolism , Cells, Cultured , Coculture Techniques , Cytokines/metabolism , Down-Regulation/drug effects , Down-Regulation/immunology , Encephalitis/chemically induced , Encephalitis/immunology , Encephalitis/prevention & control , Gliosis/chemically induced , Gliosis/immunology , Gliosis/prevention & control , Glycosylation , Humans , Injections, Intravenous , Mice , Mice, Transgenic , Microglia/metabolism , Phagocytosis/immunology , Polysaccharides/chemistry , Polysaccharides/immunology , Rats , Rats, Wistar , Treatment OutcomeABSTRACT
Immunization with amyloid-beta (Abeta) peptides, a therapeutic approach in Alzheimer's disease (AD), reduces brain Abeta, and microglial Abeta phagocytosis has been proposed as an Abeta-lowering mechanism. We transplanted rat microglia into the rat lateral ventricle just after intra-hippocampal Abeta injection, and then investigated the contribution of exogenous microglia to Abeta clearance. Migration of exogenous microglia from the lateral ventricle to Abeta plaque was detected by magnetic resonance imaging and histochemical analysis, and the clearance of Abeta was increased by transplantation. These results suggest the possible usefulness of exogenous microglia to the therapeutic approach in AD.
