Kevin Aguilar

Retinopathy is a common symptom in mitochondrial diseases, and a leading cause of blindness in working-age individuals, often arising as a consequence of diabetes. Here, we demonstrate that postnatal loss of the replicative helicase of mitochondrial DNA in the astrocytes and Müller glia induces neovascular retinopathy. In these retinas, the macroglia show pathological reactivation, leading to hallmark features of neovascularization with blood-retina-barrier leakage, secondary microgliosis, and complement cascade activation. Similar reactivation of astrocytes in the cerebral cortex does not compromise vascular integrity, indicating tissue-specific roles of mitochondrial metabolism in macroglia for vascular homeostasis. Three secreted angiogenic factors—Fgf2, Pgf, and Lcn2—known to contribute to diabetic retinopathy, were induced. Spike recordings of the most sensitive retinal ganglion cells revealed normal rod function and intact retinal coding. These findings highlight the critical role of glial mitochondrial metabolism in neovascular retinopathy, with important implications for therapy development for mitochondrial and common forms of vision loss.

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.

Background/Aims: Interleukin-6 (IL-6) is a major cytokine controlling body weight and metabolism, at least in part through actions in the central nervous system (CNS) from local sources. Methods: We herewith report results obtained in conditional IL-6 KO mice for brain cells (Il6ΔGfap and Il6ΔSyn). Results: The reporter RiboTag mouse line demonstrated specific astrocytic expression of GFAP-dependent Cre in the hypothalamus but not in other brain areas, whereas that of synapsin 1-dependent Cre was specific for neurons. Feeding a high-fat diet (HFD) or a control diet showed that Il6ΔGfap and Il6ΔSyn mice were more prone and resistant, respectively, to HFD-induced obesity. Energy intake was not altered in HFD experiments, but it was reduced in Il6ΔSyn male mice following a 24-h fast. HFD increased circulating insulin, leptin, and cholesterol levels, decreased triglycerides, and caused impaired responses to the insulin and glucose tolerance tests. In Il6ΔGfap mice, the only significant difference observed was an increase in insulin levels of females, whereas in Il6ΔSyn mice the effects of HFD were decreased. Hypothalamic Agrp expression was significantly decreased by HFD, further decreased in Il6ΔGfap, and increased in Il6ΔSyn female mice. Hypothalamic Il-6 mRNA levels were not decreased in Il6ΔSyn mice and even increased in Il6ΔGfapmale mice. Microarray analysis of hypothalamic RNA showed that female Il6ΔGfap mice had increased interferon-related pathways and affected processes in behavior, modulation of chemical synaptic transmission, learning, and memory. Conclusion: The present results demonstrate that brain production of IL-6 regulates body weight in the context of caloric excess and that the cellular source is critical.