Complement activation is implicated in driving brain inflammation, self-cell damage and progression of injury in Alzheimer's disease and other neurodegenerative diseases. Here, we investigate the impact of brain delivery of a complement-blocking antibody on neurodegeneration in an Alzheimer's mouse model. We engineered a brain-penetrant recombinant antibody targeting the pro-inflammatory membrane attack complex. Systemic administration of this antibody in APPNL-G-F mice reduced brain levels of complement activation products, demonstrating successful brain entry and target engagement. Prolonged treatment decreased synapse loss, amyloid burden and brain inflammatory cytokine levels, concomitant with cognitive improvement compared to controls. These results underscore the potential of brain-penetrant complement-inhibiting drugs as promising therapeutics, targeting downstream of amyloid plaques in Alzheimer's disease.

中文翻译：

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脑渗透补体抑制减轻阿尔茨海默病小鼠模型中的神经退行性变


补体激活与阿尔茨海默病和其他神经退行性疾病中驱动脑炎症、自身细胞损伤和损伤进展有关。在这里，我们研究了补体阻断抗体的脑递送对阿尔茨海默病小鼠模型中神经退行性变的影响。我们设计了一种靶向促炎膜攻击复合物的脑渗透性重组抗体。在 APPNL-G-F 小鼠中全身施用该抗体可降低补体激活产物的大脑水平，证明成功进入大脑和靶标参与。与对照组相比，长期治疗减少了突触丢失、淀粉样蛋白负荷和脑炎性细胞因子水平，同时伴随着认知改善。这些结果强调了脑渗透性补体抑制药物作为有前途的治疗方法的潜力，靶向阿尔茨海默病淀粉样斑块的下游。