Institute of Neurosciences, Lithuanian University of Health Sciences, Kaunas, Lithuania.
J Neurochem. 2013 Sep;126(5):604-15. doi: 10.1111/jnc.12332. Epub 2013 Jun 27.
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.
β淀粉样蛋白（Aβ）寡聚体被认为有助于阿尔茨海默病的发病机制。然而，由于强烈的大脑炎症，使用 Aβ 免疫接种的临床试验失败了，其机制尚不清楚。在这项研究中，我们测试了针对寡聚 Aβ的单克隆抗体是否会预防原代神经元-神经胶质培养物中 Aβ 寡聚体的神经毒性。然而，令人惊讶的是，这些抗体大大增加了 Aβ 的神经毒性。与单体 Aβ 片段结合的抗体对培养的神经元没有毒性，而针对其他寡聚蛋白的抗体：仓鼠多瘤病毒主要衣壳蛋白、人偏肺病毒核衣壳蛋白和麻疹病毒核衣壳蛋白，强烈增强了其抗原的神经毒性。从抗体中去除 Fc 区域或从培养物中去除小胶质细胞，可消除抗体-抗体寡聚抗原复合物的神经毒性，并且伴随着培养中小胶质细胞的炎症激活和增殖。总之，我们发现 Aβ 寡聚体或其他寡聚/多聚抗原及其特异性抗体形成的免疫复合物可通过 Fc 依赖性小胶质细胞激活导致原代神经元-神经胶质培养物中的神经元死亡和丧失。结果表明，应谨慎使用或抑制小胶质细胞激活来治疗导致针对寡聚 Aβ 或寡聚脑病毒蛋白的抗体的疗法。
