Title Antibodies dramatically increase the neurotoxicity of amyloid beta oligomers in primary neuronal-glial cultures by activating microglia /
Authors Morkūnienė, Ramunė ; Jankevičiūtė, Silvija ; Čižas, Paulius ; Dalgedienė, Indrė ; Žvirblienė, Aurelija ; Borutaitė, Vilmantė
DOI 10.1159/000381736
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Is Part of Neurodegenerative Diseases : 12th International Conference on Alzheimer's and Parkinson's Diseases and Related Neurological Disorders (AD/PD™ 2015) "Mechanisms, Clinical Strategies, and Promising Treatments of Neurodegenerative Diseases" : Nice, France, March 18-22, 2015 : Abstracts.. Basel : Karger. 2015, vol. 15, suppl. 1, p. 688-688, no. ADPD5-0591.. ISSN 1660-2854
Keywords [eng] Alzheimer disease ; Amyloid beta-peptides ; Neurons ; Cell death
Abstract [eng] Objectives. Beta amyloid (Aβ) oligomers are thought to contribute to the pathogenesis of Alzheimer's disease (AD). The success of anti-Aβ immunotherapies in preclinical studies led to the initiation of anti-Aβ in clinical trials, but halted due to brain inflammation, the mechanisms of which are poorly understood. In the present study we aimed to investigate the effects of antigen-antibody complexes formed by oligomeric Aβ and specific monoclonal antibodies in primary neuronal-glial cultures. Methods. Monoclonal antibodies generated against synthetic Aβ1-42 were preincubated with Aβ1-42 then added to cultures. The viability of neurons was examined by fluorescence microscopy. Results. We found that antibodies dramatically increased the neurotoxicity of Aβ oligomers. Complexes of antibodies plus monomeric Aβ had no effect on neuronal viability. 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 microglia. However, the preincubation of cultures with inhibitors of NADPH oxidase and NO synthase did not prevent neuronal death caused by antibody-oligomeric Aβ. Conclusions. Antibody-antigen complexes formed by Aβ oligomers or other oligomeric antigens and their specific antibodies exert strong toxic effects on neuronal cells via Fc-dependent microglial activation. Our study provides new insight into the mechanism of possible Aβ neurotoxicity in the presence of Aβ-specific antibodies in AD brain and also may be important clinically in the development of safer vaccines for AD treatment. This work was supported by the Research Council of Lithuania (grant LIG-04/2012).
Published Basel : Karger
Type Conference paper
Language English
Publication date 2015