Nimmo, Jacqui, Daskoulidou, Nikoleta, Van Pottelberge, Sophie, De Muynck, Louis and Morgan, B. Paul  ORCID: https://orcid.org/0000-0003-4075-7676
2026.
Dysregulation of complement at the synapse in P301S mice and human tauopathies.
Acta Neuropathologica Communications
14
(175)
10.1186/s40478-026-02347-2
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Abstract
Synapse loss is the best correlate of cognitive decline in neurodegenerative diseases (NDDs). In Alzheimer’s disease complement dysregulation, triggered by amyloid-β accumulation, plays a major role in synapse loss, but its contribution in other NDDs where amyloid is absent, most notably tauopathies, is elusive. Aggregation of tau is a prominent co-pathology in many NDDs and is characteristic of classical tauopathies in which amyloid pathology is lacking. Here we explore the effect of tau accumulation on complement dysregulation and its contribution to neuronal damage and synapse loss in a mouse tauopathy model harbouring the familial P301S tau mutation and post-mortem brain samples from human tauopathies. Complement gene and protein expression were analysed in P301S mice at 2, 4 and 6 M of age. Complement dysregulation was evident from qPCR analysis showing increased classical pathway (C4, C2), and complement receptor (C3ar1, Cd11b, Cd11c) gene expression in P301S mice compared to wildtype (WT). C1q protein levels were markedly increased in brain homogenates from P301S mice compared to WT, accompanied by C1q deposition on tau aggregates. Synapse loss was evident for both excitatory and inhibitory synapses and was accompanied by an increased percentage of C1q positive excitatory synapses, unaffected by proximity to tau aggregates. The classic pathway regulator CSMD1 was present on synapses and decreased on C1q positive synapses in P301S mice, implying a loss of protection from complement attack. Observations in human tauopathy brains demonstrated decreased CSMD1-labelled excitatory synapses, consistent with findings in P301S mice. These findings demonstrate that complement dysregulation occurs in areas of tau pathology and may contribute to synapse loss in tauopathies.
| Item Type: | Article |
|---|---|
| Date Type: | Published Online |
| Status: | Published |
| Schools: | Schools > Medicine |
| Publisher: | BioMed Central |
| ISSN: | 2051-5960 |
| Funders: | MRC |
| Projects: | UK DRI-3002 |
| Date of First Compliant Deposit: | 22 June 2026 |
| Date of Acceptance: | 5 June 2026 |
| Last Modified: | 04 Sep 2026 09:45 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/187673 |
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