Antibodies bound to A[beta] oligomers potentiate the neurotoxicity of A[beta] by activating microglia

Beta amyloid (A[beta]) oligomers are thought to contribute to the pathogenesis of Alzheimer's disease. However, clinical trials using A[beta] immunization were unsuccessful due to strong brain inflammation, the mechanisms of which are poorly understood. In this study we tested whether monoclonal antibodies to oligomeric A[beta] would prevent the neurotoxicity of A[beta] oligomers in primary neuronal-glial cultures. However, surprisingly, the antibodies dramatically increased the neurotoxicity of A[beta]. Antibodies bound to monomeric A[beta] fragments were non-toxic to cultured neurons, while antibodies to other oligomeric proteins: hamster polyomavirus major capsid protein, human metapneumovirus nucleocapsid protein, and measles virus nucleocapsid protein, strongly potentiated the neurotoxicity of their antigens. The neurotoxicity of antibody-oligomeric antigen complexes was abolished by removal of the Fc region from the antibodies or by removal of microglia from cultures, and was accompanied by inflammatory activation and proliferation of the microglia in culture. In conclusion, we find that immune complexes formed by A[beta] oligomers or other oligomeric/multimeric antigens and their specific antibodies can cause death and loss of neurons in primary neuronal-glial cultures via Fc-dependent microglial activation. The results suggest that therapies resulting in antibodies to oligomeric A[beta] or oligomeric brain virus proteins should be used with caution or with suppression of microglial activation. Immunization against A[beta] in Alzheimer's disease carries a significant risk of neuroinflammation, the mechanisms of which are poorly understood. In this study we show that oligomeric antigens such as A[beta] and viral proteins complexed with their specific antibodies can exert neurotoxic effects by Fc-dependent microglia activation. This suggests that therapies using antibodies against oligomeric proteins should be used with caution. [PUBLICATION ABSTRACT]