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

BACKGROUND: 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 its levels correlate with amyloid-beta (Aβ) burden and plaque deposition. 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. These findings suggest that central IL-6 overexpression may actively drive disease manifestations. However, because IL-6 can also signal through its classical membrane-bound receptor pathway, the overall impact of central IL-6 on AD pathophysiology is still not fully elucidated. MAIN TEXT: 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 promoter (GFAP-IL6), 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 observed in Tg2576 mice, with central-targeted IL-6 overexpression regulating behavior in an age- and sex-dependent manner. Increased cortical and hippocampal Aβ42/Aβ40 ratios, along with gliosis, were observed in aged female and male Tg2576 mice. Interestingly, chronic central-targeted IL-6 overexpression increased cortical and hippocampal Aβ42/Aβ40 ratios while inducing a differential distribution and/or reactivity of astrocytes and microglia in aged Tg2576 mice. In particular, central-targeted IL-6 overexpression resulted in increased overall gliosis in the cortical and hippocampal parenchyma but reduced gliosis in the vicinity of cortical and hippocampal amyloid plaques. 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. CONCLUSIONS: 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.