Targeting terminal pathway reduces brain complement activation, amyloid load and synapse loss, and improves cognition in a mouse model of dementia

Zelek, Wioleta M., Bevan, Ryan J. ORCID: https://orcid.org/0000-0002-2557-2887 and Morgan, Bryan Paul ORCID: https://orcid.org/0000-0003-4075-7676 2024. Targeting terminal pathway reduces brain complement activation, amyloid load and synapse loss, and improves cognition in a mouse model of dementia. Brain, Behavior, and Immunity 118 , pp. 355-363. 10.1016/j.bbi.2024.03.017

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Abstract

Complement is dysregulated in the brain in Alzheimer’s Disease and in mouse models of Alzheimer’s disease. Each of the complement derived effectors, opsonins, anaphylatoxins and membrane attack complex (MAC), have been implicated as drivers of disease but their relative contributions remain unclarified. Here we have focussed on the MAC, a lytic and pro-inflammatory effector, in the AppNL−G−F mouse amyloidopathy model. To test the role of MAC, we back-crossed to generate AppNL−G−F mice deficient in C7, an essential MAC component. C7 deficiency ablated MAC formation, reduced synapse loss and amyloid load and improved cognition compared to complement-sufficient AppNL−G−F mice at 8–10 months age. Adding back C7 caused increased MAC formation in brain and an acute loss of synapses in C7-deficient AppNL−G−F mice. To explore whether C7 was a viable therapeutic target, a C7-blocking monoclonal antibody was administered systemically for one month in AppNL−G−F mice aged 8–9 months. Treatment reduced brain MAC and amyloid deposition, increased synapse density and improved cognitive performance compared to isotype control-treated AppNL−G−F mice. The findings implicate MAC as a driver of pathology and highlight the potential for complement inhibition at the level of MAC as a therapy in Alzheimer’s disease.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	0889-1591
Date of First Compliant Deposit:	22 March 2024
Date of Acceptance:	11 March 2024
Last Modified:	02 Apr 2024 13:30
URI:	https://orca.cardiff.ac.uk/id/eprint/167504

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