Chronic central-targeted Interleukin-6 overexpression promotes hippocampal and cortical neuropathology in the Tg2576 mouse model of Alzheimer’s disease

Interleukin-6 (IL-6) is a cytokine detected in the brains and peripheral fluids of both Alzheimer’s disease (AD) patients and mouse models, where it colocalizes with amyloid-beta (Aβ) levels and amyloid plaques. Interestingly, IL-6 deficiency ameliorates cognitive deficits and attenuates hippocampal neuroinflammation, whereas astrocyte-targeted IL-6 signaling via its soluble receptor accentuates pathological features in AD mouse models. This finding suggests that central IL-6 overexpression may actively drive disease manifestations. However, because IL-6 also signals through its classical membrane-bound receptor pathway, the overall impact of central IL-6 on Alzheimer’s disease pathophysiology is still not fully elucidated. To explore the contribution of central IL-6 overexpression in modulating AD-related mortality, metabolic, behavioral and neuroinflammatory changes in the hippocampus and cortex, we crossed a transgenic mouse model (Tg2576) of Aβ-driven amyloidosis with mice expressing IL-6 under the Glial Fibrillary Acidic Protein (GFAP) promoter, which predominantly targets astrocytes. Chronic IL-6 overexpression reduced inguinal white adiposity in both males and females and decreased body weight in females. Early behavioral alterations were also observed, along with increased cortical and hippocampal Aβ ₄₂ /Aβ ₄₀ ratios and gliosis in aged Tg2576 female and male mice. Interestingly, chronic IL-6 overexpression also decreased cortical and hippocampal periplaque astrocytosis and microgliosis, suggesting a heterogeneous response of astrocytes and microglia to IL-6 overexpression within the primary regions affected by this pathology. Finally, cortical transcriptomic profiling in Tg2576 mice revealed widespread changes in immune, synaptic, and stress response pathways in response to chronic IL-6 overexpression, with cortical neuroinflammatory and neurotransmission-associated gene networks showing sex-dependent differences. Our findings emphasize that chronic central-targeted IL-6 overexpression shapes the cortical and hippocampal molecular landscape underlying amyloidosis in both male and female Tg2576 mice. Thereby, we propose IL-6 as a potential target for future AD therapeutic strategies.