Zelek, Wioleta M;
Bevan, Ryan J;
Nimmo, Jacqui;
Dewilde, Maarten;
De Strooper, Bart;
Morgan, B Paul;
(2024)
Brain-penetrant complement inhibition mitigates neurodegeneration in an Alzheimer's disease mouse model.
Brain
10.1093/brain/awae278.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Brain-penetrant complement inhibition mitigates neurodegeneration in an Alzheimer's disease mouse model |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/brain/awae278 |
| Publisher version: | http://dx.doi.org/10.1093/brain/awae278 |
| Language: | English |
| Additional information: | © The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | neuroinflammation, therapy, drug delivery, blood–brain barrier, mouse model |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10197894 |
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