Complement dysregulation in human tauopathies

Nimmo, Jacqui, Keat, Samuel, De Muynck, Louis and Morgan, B. Paul ORCID: https://orcid.org/0000-0003-4075-7676 2025. Complement dysregulation in human tauopathies. Brain Pathology , e70017. 10.1111/bpa.70017

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Abstract

Dysregulation of the complement system plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). In post‐mortem AD brains, complement is deposited in and around amyloid plaques, and peri‐plaque complement activation drives synapse loss in AD mouse models. Studies to date have focused on amyloid pathology; however, aggregated tau is also involved in neuronal loss in AD. Primary tauopathies are characterised by tau pathology in the absence of amyloid. The role of complement in human tauopathies remains largely unexplored. Here, we address this knowledge gap by assessing complement activation in human tauopathy brains using immunohistochemistry and well‐characterised detection tools. Post‐mortem pre‐frontal cortex was obtained from three tauopathy subtypes, Pick's disease (PiD), globular glial tauopathy (GGT) and corticobasal degeneration (CBD) (3–5 cases each). C1q and the complement activation markers iC3b and terminal complement complex (TCC) were assessed by immunohistochemistry and were elevated in all tauopathy cases compared to controls, with C1q and C3b/iC3b deposition particularly prominent on neurons, demonstrating complement activation on these cells. TCC deposits were present on and adjacent neurons in all tauopathy brains examined and were significantly increased compared to controls in CBD and GGT. Uniquely in GGT, abundant deposition of C3b/iC3b on myelin was also observed, implicating complement in GGT‐associated demyelination. To validate these findings, complement proteins (C1q, C3, factor B), regulators (factor I, clusterin) and activation products (Ba, C3b/iC3b, and TCC) were measured in brain homogenates by ELISA, revealing significant elevation in C3b/iC3b, Ba, and FI in CBD and GGT cases compared to controls. Together, our data demonstrate complement activation on and adjacent neurons in post‐mortem brains from all tauopathy subtypes.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Wiley
ISSN:	1015-6305
Date of First Compliant Deposit:	28 May 2025
Date of Acceptance:	5 May 2025
Last Modified:	28 May 2025 09:30
URI:	https://orca.cardiff.ac.uk/id/eprint/178552

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