title: Antibodies bound to Aβ oligomers potentiate the neurotoxicity of Aβ by activating microglia.
abstract: Beta amyloid (Aβ) oligomers are thought to contribute to the pathogenesis of Alzheimer’s disease. However, clinical trials using Aβ 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 Aβ would prevent the neurotoxicity of Aβ oligomers in primary neuronal-glial cultures. However, surprisingly,the antibodies dramatically increased the neurotoxicity of Aβ. Antibodies bound to monomeric Aβ 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-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 Aβ 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 Aβ or oligomeric brain virus proteins should be used with caution or with suppression of microglial activation.
authors.affiliation: Institute of Neurosciences, Lithuanian University of Health Sciences, Kaunas, Lithuania. ramunem@med.kmu.lt
authors.forename: Ramune
authors.initials: R
authors.lastname: Morkuniene
authors.forename: Aurelija
authors.initials: A
authors.lastname: Zvirbliene
authors.forename: Indre
authors.initials: I
authors.lastname: Dalgediene
authors.forename: Paulius
authors.initials: P
authors.lastname: Cizas
authors.forename: Silvija
authors.initials: S
authors.lastname: Jankeviciute
authors.forename: Giedre
authors.initials: G
authors.lastname: Baliutyte
authors.forename: Ramunas
authors.initials: R
authors.lastname: Jokubka
authors.forename: Marija
authors.initials: M
authors.lastname: Jankunec
authors.forename: Gintaras
authors.initials: G
authors.lastname: Valincius
authors.forename: Vilmante
authors.initials: V
authors.lastname: Borutaite
mesh_terms: D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000633:toxicity*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; antibodies; beta amyloid; neurons; neurotoxicity; oligomers