Carla Canal

Interleukin-6 (IL-6) is a pleiotropic cytokine implicated in neuroinflammation and Alzheimer’s disease (AD) pathophysiology, but its contribution to the phenotype associated with amyloid precursor protein (APP) overexpression remains unclear. Here, we investigated the effects of systemic IL-6 deficiency in Tg2576 mice by assessing survival, physiological parameters, behavior, learning and memory, APP/amyloid-β (Aβ)-related pathology, and gliosis in young and aged male and female mice. In this specific cohort of animals, Tg2576 mice exhibited reduced survival and body weight, together with age- and sex-dependent alterations in behavioral and cognitive parameters. Notably, despite increased circulating Aβ40 and Aβ42, Aβ40 and Aβ42 were undetectable in the brain, and amyloid plaques were absent in Tg2576 mice compared with plaque-positive control mice. IL-6 deficiency partially rescued several of these phenotypes, particularly in females. Thus, the APP overexpression-associated phenotype observed here occurred in the absence of detectable cerebral amyloidosis, highlighting that APP overexpression-associated alterations can manifest independently of amyloid plaque deposition. Together, our findings underscore the complexity of AD pathogenesis and emphasize the multifaceted nature of IL-6 in both physiological and neurodegenerative processes, particularly in the context of AD.

Summary: 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.