Losing cGAS Drives Microglial Decline and Progressive Neurodegeneration in Mice

The cGAS-STING pathway has earned a reputation as an inflammatory villain in the aging brain, but a new study suggests the enzyme cGAS may also be an unsung guardian of brain health. In mice lacking cGAS, microglia — the brain’s resident immune cells — show lasting signs of dysfunction, and the animals develop progressive neurodegeneration and memory deficits starting in early adulthood, all without any overt disease challenge.

The research, published as an open-access article in Biological Research on 28 August 2026, was led by Paola Murgas and colleagues, with Gonzalo I. Cancino as senior author. The team set out to answer a question that has been largely overshadowed by the pathway’s inflammatory fame: does cGAS do anything useful in microglia under normal, physiological conditions?

Microglia are the predominant cGAS-expressing cell type in the central nervous system, which made them the natural starting point. The authors hypothesized that the constitutive absence of cGAS might compromise microglial competence and neuro-immune integrity across the lifespan, independently of pathology. Their findings, they argue, position cGAS deficiency as a potential model of accelerated microglial aging.

The first clue came from flow cytometric analysis of wild-type mouse brains. The researchers measured cGAS expression in three immune populations: CD45low/CD11bhigh microglia, CD45high/CD11bhigh macrophages, and CD45high/CD11b− lymphocytes. The most notable transition in expression occurred between 3 and 6 months of age, suggesting that high cGAS availability may be restricted to a defined window of early adulthood.

That developmental decline was mirrored at the protein level. Western blot and immunofluorescence analyses confirmed a marked reduction in total cGAS and STING protein in aged wild-type brains, reinforcing the idea that the pathway’s presence in the brain immune compartment naturally wanes with age.

What happens when cGAS is missing from the start? The cGAS knockout mice told a striking story. They exhibited persistent alterations in exploratory behavior at every age examined, alongside progressive deficits in recognition and spatial memory that emerged from adulthood onward. Behavior, in other words, deteriorated along a timeline that tracked the loss of microglial support rather than any acute insult.

The structural correlate was equally clear. Beginning at 3 months of age, the knockout animals showed an increased area of neurodegeneration in the somatosensory cortex and hippocampus. Microglial analysis in both regions revealed a consistent reduction in cell density, an altered morphological profile, and reduced Iba1 signal — a hallmark marker of microglial presence and activation state.

Functional profiling deepened the picture. Flow cytometry showed a sustained downregulation of MHCII, CD86, and CD206 on cGAS-deficient microglia, a molecular signature the authors interpret as functional hyporesponsiveness. In practical terms, the cells were not simply fewer and structurally altered; they appeared blunted in their capacity to respond, undermining the surveillance and coordination roles microglia normally perform.

The peripheral immune interface was also disrupted, though in a region-specific way. Macrophage infiltration remained unaffected in the cortex but was reduced in the hippocampus of knockout mice. Meanwhile, the knockout animals failed to sustain the age-related increase in lymphocyte recruitment observed in wild-type animals, despite showing elevated lymphocyte levels at a young age — an early surplus that could not be maintained over time.

The authors conclude that cGAS may play an essential homeostatic role in maintaining microglial competence and neuro-immune coordination throughout the lifespan. They propose that the early physiological decline of cGAS in brain immune populations, combined with the broad neuroimmune dysfunction seen in its absence, may help explain the brain’s capacity to sustain immune surveillance and resist age-related neurodegeneration. As with any mouse model, the findings are associative and preclinical, and whether the same homeostatic role operates in the human brain remains an open question. Still, the study reframes a pathway best known for driving inflammation as one whose early-life presence may be quietly protecting the aging brain.

Subject of Research: The homeostatic role of the cGAS-STING pathway in microglial function and neurodegeneration in mice

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

Article References: Murgas, P., Mesa, S., Escandón, M., Matus, M. S., & Cancino, G. I. (2026). Loss of cGAS alters microglial homeostasis, promotes progressive neurodegeneration, and impairs neuroimmune coordination. Biological Research. https://doi.org/10.1186/s40659-026-00719-5

Image Credits: AI Generated

DOI: 10.1186/s40659-026-00719-5

Keywords: cGAS, STING, microglia, neurodegeneration, neuroinflammation, hippocampus, somatosensory cortex, MHCII, lymphocytes, brain aging, knockout mice, Biological Research