Enhanced classical complement pathway activation and altered phagocytosis signaling molecules in human epilepsy

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Microglia-mediated neuroinflammation is linked to epilepsy.
• The role of microglial phagocytosis in epilepsy remains unclear.
• Complement proteins (C1q-C3) are implicated in synaptic pruning and altered in epilepsy models.

Purpose of the Study:

• To investigate the role of complement proteins and phagocytic signaling in the synaptodendritic pathology of human refractory epilepsy.
• To determine protein levels of classical complement proteins (C1q-C3) and phagocytosis-related molecules in epilepsy.

Main Methods:

• Western blotting and immunostaining were used on cortical brain samples from refractory epilepsy (RE) and non-epileptic lesion (NE) patients.
• Protein levels of C1q, C3, MerTK, Trem2, Pros1, and cleaved-caspase 3 were quantified.
• C1q distribution and co-localization with microglia and dendrites were examined.

Main Results:

• Refractory epilepsy samples showed significantly increased C1q and iC3b protein levels.
• Decreased levels of Trem2 and Pros1 were observed in RE samples compared to NE.
• C1q localized to microglia and dendrites, with increased microglia-dendritic interactions in RE tissue.

Conclusions:

• Aberrant phagocytic signaling, particularly involving complement C1q, is present in human refractory epilepsy.
• Altered phagocytic pathways may contribute to synaptic elimination and impaired debris clearance in epilepsy.
• Further studies are needed to confirm if complement signaling drives epilepsy-related hyperexcitability.