C3 and C3a as indicators of complement dysregulation in tauopathies and FTLD-associated disorders

Topic: Brain proteins, microglia and lab models

Dementia encompasses a range of neurodegenerative diseases (NDDs) presenting with progressive decline in memory, cognition, language and ability to complete daily tasks. Whilst Alzheimer’s disease (AD) is the most common form of dementia, less prevalent subtypes include frontotemporal lobar degenerative associated disorders (FTLD) frontotemporal dementia (FTD), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). FTLD are NDDs characterised by progressive atrophy and neuronal loss in brain frontal and temporal lobes, predominately affecting behaviour, language and cognition. Of these, FTLD, CBS and PSP are primary tauopathies, pathologically classified by predominant accumulation of aggregates of tau, a microtubule-associated protein responsible for mediating intracellular transport and structure. Some FTD subtypes, such as Pick’s disease, are also defined by tau pathology. Although complement dysregulation is broadly accepted as a feature of AD, this has not been convincingly shown in tauopathies and FTLD. Here we measured a panel of complement biomarkers in serum from FTLD and tauopathy cases and compared these with non-demented matched controls (HC). In-house ELISAs were used to quantify twelve complement analytes, comprising activation products (C3a, iC3b, TCC), regulators (Factor H (FH), Properdin, Clusterin) and components (C1q, C3, FB, C5, C7, C9) in serum samples. Samples were matched for age and sex from FTLDs: CBS (n = 16), FTD (n = 57), PSP (n = 42), healthy controls (HC; n = 41). Compared to HC, C3, C3a and properdin were elevated in FTLD (p = 0.0002, p = 0.0187, p = 0.0451 respectively). Other complement analytes were not significantly different between FTLD and HC samples. Subgroup analysis demonstrated significantly higher C3 and C3a compared to HC in FTD (p < 0.00001 and p = 0.0455 respectively) and PSP (p = 0.0051 and p = 0.0179 respectively) but not CBS, while properdin was significantly increased only in FTD cases (p = 0.0097). The data demonstrates a degree of complement dysregulation in tauopathies and FTLD across the different disease subtypes with C3, C3a and properdin levels significantly different to matched controls. These findings suggest dysregulation in the alternative pathway and lead us to suggest that complement dysregulation represents a potential therapeutic target for FTLD and tauopathies.

Key findings

• Compared to HC, C3, C3a and properdin were elevated in FTLD (p = 0.0002, p = 0.0187, p = 0.0451 respectively).
• Other complement analytes were not significantly different between FTLD and HC samples.
• Subgroup analysis demonstrated significantly higher C3 and C3a compared to HC in FTD (p < 0.00001 and p = 0.0455 respectively) and PSP (p = 0.0051 and p = 0.0179 respectively) but not CBS, while properdin was significantly increased only in FTD cases (p = 0.0097).
• The data demonstrates a degree of complement dysregulation in tauopathies and FTLD across the different disease subtypes with C3, C3a and properdin levels significantly different to matched controls.
• These findings suggest dysregulation in the alternative pathway and lead us to suggest that complement dysregulation represents a potential therapeutic target for FTLD and tauopathies.

Why it matters

In serum from people with frontotemporal lobar degeneration and tauopathies, levels of C3, C3a, and properdin were elevated compared with non-demented controls, while other complement analytes did not differ significantly. Subgroup analysis found higher C3 and C3a in frontotemporal dementia and progressive supranuclear palsy but not corticobasal syndrome.

Study details

• Participants16
• Evidence strengthLow

Read the original

• DOI: 10.1016/j.imbio.2025.152946
• Original source →
• Free full text: Immunobiology →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{nicholls2025-1226f07b,
  author  = {Nicholls, Laura E. and Nimmo, Jacqui and Cooke, Rebekah S. and Baggott, Taine J. and Bright, Matthew and Byrne, Robert A.J. and Fenn, Gareth D. and Keat, Samuel and others},
  title   = {{C3 and C3a as indicators of complement dysregulation in tauopathies and FTLD-associated disorders}},
  journal = {Immunobiology},
  year    = {2025},
  doi     = {10.1016/j.imbio.2025.152946},
  url     = {https://doi.org/10.1016/j.imbio.2025.152946}
}

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