DISTINCT MICROGLIAL RESPONSES ACROSS THE HIPPOCAMPUS IN TEMPORAL LOBE EPILEPSY: LINKS TO TAU AND COGNITIVE DYSFUNCTION

Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy in adults and is frequently associated with cognitive impairment. Emerging evidence suggests that epilepsy shares pathophysiological mechanisms with neurodegenerative diseases. Microglia respond to chronic seizures, but their phenotypic signature and potential role in proteinopathies progression and cognitive impairment are unclear in TLE. This study aimed to characterize microglial markers (Iba-1 and CD68), tau pathology (p-tau), and microglial morphology in the hippocampus of individuals with mesial TLE and investigate their associations with cognitive performance. Hippocampal post-surgical samples from TLE patients were compared with post-mortem hippocampal tissue of controls from the Aging Biobank (n=20/group). Cognitive performance was evaluated pre-surgically using neuropsychological tests. Iba-1, CD68, and p-tau were evaluated by immunohistochemistry and quantified using digital morphometry in the hippocampal subregions CA1, CA2–3, CA4, DG, and SUB. Microglial morphology was assessed using Sholl analysis.. Iba-1 and CD68 expressions were increased across all hippocampal subregions in TLE. P-tau was also increased in the whole hippocampus and positively correlated with Iba-1 in CA4 and DG and with CD68 in CA1, CA2-3, and CA4. The sholl analysis demonstrated a less ramified profile of microglia in TLE. Regarding cognitive outcomes, regression models adjusted for hippocampal sclerosis type, disease duration, and seizure frequency showed that higher Iba-1 expression was associated with poorer attention and global cognition, in a region-dependent manner, while increased expression of CD68 was associated with poorer performance in attention, visual and verbal memory, and global cognition, also region-dependent. These findings support the involvement of microglia, with region-specific responses across hippocampal subregions, in TLE-related tauopathy and cognitive impairment.