Neuroinflamação e taupatia na epilepsia do lobo temporal: associação entre a modulação microglial pela via TREM2/DAP12 e declínio cognitivo

Abstract

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy in adults and is associated with a high rate of drug resistance. Neuroinflammation is intrinsically involved in the pathophysiology of the disease, leading to cognitive outcomes. Recent evidence suggests that microglia and the deposition of hyperphosphorylated Tau protein (p-Tau) play important roles in the development and progression of the cognitive impairment associated with TLE; however, the underlying mechanisms remain poorly understood. The present study investigated the expression of the microglial markers Iba-1, TREM2, DAP12, and CD68, p-Tau deposition, microglial morphological alterations, and their associations with cognitive performance in patients with TLE. Human hippocampal samples were obtained from patients who underwent selective amygdalohippocampectomy at Hospital Felício Rocho (Belo Horizonte, Brazil) and Hospital das Clínicas of the Federal University of Minas Gerais (UFMG) (Belo Horizonte, Brazil), and were compared with hippocampal samples from control individuals obtained from the Biobank for Aging Studies of the University of São Paulo (USP) (São Paulo, Brazil). The expression of the aforementioned proteins was evaluated by immunohistochemistry and immunofluorescence in the hippocampal subregions CA1, CA2–3, CA4, dentate gyrus (DG), and subiculum (SUB), and quantified using semi-automated digital morphometry. The morphology of Iba-1⁺ cells was assessed using Sholl analysis and the ratio between cell body area and total cell area. Linear regression models adjusted for clinical variables were also developed to evaluate associations between the molecular markers and the clinical and cognitive data obtained from preoperative neuropsychological assessments. The results demonstrated increased expression of Iba-1 and CD68 across all hippocampal subregions in TLE, accompanied by higher cell density, reduced branching complexity, and a proportional increase in microglial cell body size, indicating a more amoeboid and phagocytic microglial phenotype. TREM2 and DAP12 expression was increased in a region-dependent manner, particularly in CA1, DG, and SUB. Immunofluorescence confirmed the colocalization of TREM2 and CD68 with Iba-1, reinforcing the hyperactivated microglial profile in TLE. p-Tau deposition was increased in all hippocampal subregions and was positively associated with microglial markers, suggesting an interaction between tauopathy and neuroinflammation. Furthermore, higher levels of p-Tau, Iba-1, TREM2, and CD68 were associated with poorer performance across different cognitive domains in distinct hippocampal subregions, with the most frequent associations observed with TREM2. Collectively, these findings indicate the presence of tauopathy in patients with TLE younger than 60 years and suggest that chronic microglial activation, accompanied by morphological alterations and enhanced phagocytic activation, responds to this proteinopathy, thereby contributing to cognitive impairment. These results reinforce the close interaction between neuroinflammation and neurodegeneration in the pathophysiology of TLE and highlight the TREM2/DAP12 pathway as a potential target for future mechanistic and therapeutic investigations.