Brain-penetrant complement inhibition mitigates neurodegeneration in an Alzheimer's disease mouse model

脑渗透性补体抑制可减轻阿尔茨海默病小鼠模型中的神经退行性

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作者:Wioleta M Zelek, Ryan J Bevan, Jacqui Nimmo, Maarten Dewilde, Bart De Strooper, Bryan Paul Morgan

Abstract

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.

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