Zelek Wioleta M, Bevan Ryan J, Nimmo Jacqui, Dewilde Maarten, De Strooper Bart, Morgan Bryan Paul
School of Medicine, UK Dementia Research Institute Cardiff, Cardiff University, Cardiff CF14 4XN, UK.
Therapeutic and Diagnostic Antibodies, Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven 3000, Belgium.
Brain. 2025 Mar 6;148(3):941-954. doi: 10.1093/brain/awae278.
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.
补体激活与阿尔茨海默病和其他神经退行性疾病中的脑炎症、自身细胞损伤及损伤进展有关。在此，我们研究了在阿尔茨海默病小鼠模型中，脑内递送补体阻断抗体对神经退行性变的影响。我们构建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小鼠中全身给予该抗体可降低脑内补体激活产物水平，表明其成功进入脑内并与靶点结合。与对照组相比，长期治疗可减少突触丢失、淀粉样蛋白负荷和脑内炎性细胞因子水平，同时改善认知功能。这些结果强调了脑渗透性补体抑制药物作为有前景的治疗方法的潜力，其靶向阿尔茨海默病中淀粉样斑块的下游环节。
