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

Zelek, Wioleta M., Bevan, Ryan J. ORCID: https://orcid.org/0000-0002-2557-2887, Nimmo, Jacqui, Dewilde, Maarten, De Strooper, Bart and Morgan, B. Paul ORCID: https://orcid.org/0000-0003-4075-7676 2024. Brain-penetrant complement inhibition mitigates neurodegeneration in an Alzheimer's disease mouse model. Brain 10.1093/brain/awae278

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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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Medicine
Publisher:	Oxford University Press
ISSN:	0006-8950
Date of First Compliant Deposit:	13 September 2024
Date of Acceptance:	29 August 2024
Last Modified:	08 Nov 2024 04:15
URI:	https://orca.cardiff.ac.uk/id/eprint/172080

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