Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA.
Acta Neuropathol Commun. 2022 Aug 17;10(1):116. doi: 10.1186/s40478-022-01416-6.
Multiple studies have recognized the involvement of the complement cascade during Alzheimer's disease pathogenesis. However, the specific role of C5a-C5aR1 signaling in the progression of this neurodegenerative disease is still not clear. Furthermore, its potential as a therapeutic target to treat AD still remains to be elucidated. Canonically, generation of the anaphylatoxin C5a as the result of complement activation and interaction with its receptor C5aR1 triggers a potent inflammatory response. Previously, genetic ablation of C5aR1 in a mouse model of Alzheimer's disease exerted a protective effect by preventing cognitive deficits. Here, using PMX205, a potent, specific C5aR1 antagonist, in the Tg2576 mouse model of Alzheimer's disease we show a striking reduction in dystrophic neurites in parallel with the reduced amyloid load, rescue of the excessive pre-synaptic loss associated with AD cognitive impairment and the polarization of microglial gene expression towards a DAM-like phenotype that are consistent with the neuroprotective effects seen. These data support the beneficial effect of a pharmacological inhibition of C5aR1 as a promising therapeutic approach to treat Alzheimer's disease. Supportive of the safety of this treatment is the recent FDA-approval of another other C5a receptor 1 antagonist, Avacopan, as a treatment for autoimmune inflammatory diseases.
多项研究已经认识到补体级联反应在阿尔茨海默病发病机制中的参与。然而，C5a-C5aR1 信号在这种神经退行性疾病进展中的具体作用仍不清楚。此外，其作为治疗 AD 的治疗靶点的潜力仍有待阐明。通常，补体激活和与其受体 C5aR1 相互作用导致过敏毒素 C5a 的产生会引发强烈的炎症反应。先前，在阿尔茨海默病的小鼠模型中，通过遗传敲除 C5aR1 可以发挥保护作用，防止认知缺陷。在这里，我们使用 PMX205，一种有效的、特异性的 C5aR1 拮抗剂，在阿尔茨海默病的 Tg2576 小鼠模型中，我们发现与淀粉样蛋白负荷降低平行的是，神经突的进行性病变显著减少，与 AD 认知障碍相关的过度突触前丢失得到挽救，小胶质细胞基因表达向 DAM 样表型极化，这与观察到的神经保护作用一致。这些数据支持 C5aR1 药理学抑制作为治疗阿尔茨海默病的一种有前途的治疗方法的有益效果。支持这种治疗安全性的是，另一种 C5a 受体 1 拮抗剂 Avacopan 最近被 FDA 批准用于治疗自身免疫性炎症性疾病。
