Loss of cGAS alters microglial homeostasis, promotes progressive neurodegeneration, and impairs neuroimmune coordination

Abstract

The cGAS-STING pathway has been extensively studied as a driver of neuroinflammation in the context of brain aging and neurodegeneration. However, whether cGAS plays a homeostatic role in microglial function under physiological conditions — and how its expression levels evolve at progressive ages in specific brain immune populations — remains poorly understood. Given that microglia represent the predominant cGAS-expressing cell type in the central nervous system, we hypothesized that its constitutive absence may compromise microglial competence and neuro-immune integrity across different ages, independently of overt pathology. Flow cytometric analysis of WT mouse brains revealed that cGAS expression levels in CD45 low /CD11b high microglia, CD45 high /CD11b high (macrophages), and CD45 high /CD11b − (lymphocytes) cells undergo the most notable transition occurring between 3 and 6 months, suggesting that high cGAS availability may be restricted to a defined window of early adulthood. Western blot and immunofluorescence analyses confirmed a marked reduction in total cGAS and STING protein levels in aged WT brains. In parallel, cGASKO mice exhibited persistent alterations in exploratory behavior across all ages examined, alongside progressive deficits in recognition and spatial memory emerging from adulthood. These behavioral alterations were accompanied by an increased area of neurodegeneration in the somatosensory cortex and hippocampus from 3 months of age. Microglial analysis revealed a consistent reduction in cell density, morphological profile, and reduced Iba1 signal in both brain regions. Flow cytometric profiling showed a sustained downregulation of MHCII, CD86, and CD206 in cGASKO microglia, suggesting functional hyporesponsiveness. Finally, while macrophage infiltration remained unaffected in cortex but reduced in hippocampus, cGASKO mice failed to sustain the age-related increase in lymphocytes population recruitment observed in WT animals, despite showing elevated lymphocyte levels at young age. These findings suggest that cGAS may play an essential homeostatic role in maintaining microglial competence and neuro-immune coordination throughout the lifespan. The early physiological decline of cGAS in brain immune populations, combined with the broad neuroimmune dysfunction observed in cGASKO mice, raises the possibility that this early window of cGAS expression may contribute to the brain's capacity to sustain immune surveillance and resist age-related neurodegeneration. Collectively, these data position cGAS deficiency as a potential model of accelerated microglial aging with implications for understanding the cellular mechanisms underlying brain vulnerability during physiological senescence.