EXPLORING THE ROLE OF INTERLEUKIN-6 SIGNALING IN A THIRD-GENERATION MOUSE MODEL OF ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is a complex, multifactorial neurodegenerative disorder whose initiating mechanisms remain incompletely understood. Although amyloid pathology and tau dysfunction constitute the main hallmarks of the disease, the molecular processes that drive the transition from physiological aging to neurodegeneration are still unclear. Neuroinflammation is one of the main pathological processes studied in this context, representing a major metabolic disturbance in the brain. Multiple molecular factors may contribute to disease progression. Among them, IL-6 signaling is considered one of the major orchestrators of neuroinflammatory responses in the central nervous system, although its specific contribution to Alzheimer’s disease progression remains unclear.To investigate the potential modulatory role of interleukin-6 (IL-6) signaling in AD progression, we used a third-generation knock-in mouse model carrying the Iberian and Swedish mutations in the App gene together with a Psen1 mutation. This AD model was combined with two additional transgenic lines: one overexpressing IL-6 and another expressing sgp130Fc, a selective inhibitor of IL-6 trans-signaling. Male and female mice were studied at 10 months of age.Preliminary results from behavioral characterization suggest group-dependent differences primarily in exploratory behavior, assessed using the Hole Board test, and in anxiety-related and aversive behavior, evaluated with the Elevated Plus Maze. In contrast, spatial learning and memory performance, assessed by the Morris Water Maze and the Novel Object Location Test, appears less affected across genotypes.Transcriptomic analyses of hippocampal and cortical tissue are currently ongoing and aim to provide insight into how IL-6 signaling may influence molecular pathways associated with vulnerability in AD.