Scientists have demonstrated that knocking out part of the cGAS-STING DNA-sensing pathway slows disease progression in a mouse model of Alzheimerβs, calming down microglia and protecting neurons [1].
STING operation
Inflammation is central to the pathogenesis of Alzheimerβs disease [2], which is accompanied by the accumulation of extracellular plaques of the misfolded protein amyloid beta (AΞ²), soluble and insoluble AΞ² oligomers (short chunks), and tangles of tau protein. Some oligomers and tau tangles accumulate inside cells, causing stress.
Chronic amyloid/tau stress is thought to damage nuclear DNA and mitochondria, causing DNA to spill into the cytosol. This, in turn, leads to the activation of a DNA-sensing inflammatory pathway with the protein STING as its major regulator. When activated, the brainβs resident immune cells (microglia) amplify inflammation, further damaging neurons and their surrounding environment.
Previous research has found that inhibiting STING with a small molecule, H-151, lowers amyloid burden but also hits multiple off-target receptors. In this new study published in Alzheimerβs & Dementia, a team at the University of Virginia has delivered the first clean genetic test of whether the cGAS-STING DNA-sensing pathway actively drives amyloid pathology in Alzheimer’s.
The researchers crossed a popular mouse model of Alzheimerβs (5xFAD), which exhibits early amyloid accumulation, with another strain in which STING was genetically knocked out. They then subjected the progeny to various tests. Unfortunately, the scientists only used female mice, which might impact the studyβs generalizability.
Calmer microglia, healthier neurons
At four months old, a stage when soluble AΞ² is high in this model but plaques have only begun to spread, these mice underwent the Morris water maze test. STING-deficient 5xFAD animals found the hidden platform faster and lingered longer in the target quadrant during the probe, pointing to an early cognitive rescue, even before the appearance of clear Alzheimerβs symptoms.
Further tests showed that soluble and insoluble AΞ²42, a particularly harmful AΞ² species, fell by roughly 30-40% in STING-deficient brains. Plaque counts and coverage dropped in three brain regions: cortex, hippocampus, and subiculum.
Activated microglia are linked to a stronger and neuron-damaging immune response. In mice lacking STING, microglia were more subdued, covering less tissue and clustering less tightly around plaques. Their morphology also suggested a “resting” rather than an “attack” phenotype. Single-nucleus RNA sequencing of about 6,000 cortical cells showed that STING-null microglia turned off some pro-inflammatory genes while boosting markers of homeostasis.
These results strongly suggest that STING deletion tones down microglial activation. The researchers note that βmany of the top genetic risk factors linked to late-onset AD are immune genes and/or are expressed predominantly by microglia in the brain.β
Neurons, too, were in better shape in STING-deficient animals, showing healthier neurites, less oxidative stress, and less cell death at both five and nine months. That sustained drop means that removing STING not only cools inflammation but also protects neurons from structural and oxidative harm over time.
Relevant to other diseases
βOur findings demonstrate that the DNA damage that naturally accumulates during aging triggers STING-mediated brain inflammation and neuronal damage in Alzheimer’s disease,β said Dr. John Lukens, director of UVA’s Harrison Family Translational Research Center in Alzheimer’s and Neurodegenerative Diseases. βThese results help to explain why aging is associated with increased Alzheimer’s risk and uncover a novel pathway to target in the treatment of neurodegenerative diseases.β
βWe found that removing STING dampened microglial activation around amyloid plaques, protected nearby neurons from damage, and improved memory function in Alzheimer’s model mice,β said researcher Jessica Thanos, part of UVA’s Department of Neuroscience and Center for Brain Immunology and Glia (BIG Center). βTogether, these findings suggest that STING drives detrimental immune responses in the brain that exacerbate neuronal damage and contribute to cognitive decline in Alzheimer’s disease.β
cGAS-STING pathway has been linked to other neurodegenerative diseases, such as amyotrophic lateral sclerosis [3] and Parkinsonβs, as well as to many inflammatory diseases, making this studyβs findings potentially even more important. However, more rigorous research will be needed. Along with numerous strengths, this study also had several limitations, apart from using only female mice. For instance, the researchers did not assess cognitive function later in life, possibly due to the technical difficulties of breeding an additional cohort.
βWe are only beginning to understand the complex role of innate immune activation in the brain, and this is especially true in both normal and pathological aging,β Thanos said. βIf we can pinpoint which cells and signals sustain that activation, we will be in a much better position to intervene effectively in disease.β
βOur hope is that this work moves us close to finding safer and more effective ways to protect the aging brain, as there is an urgent need for treatments that can slow or prevent neuronal damage in Alzheimer’s,β Lukens added. βShedding light on how STING contributes to that damage may help us target similar molecules and ultimately develop effective disease-modifying treatments.β
Literature
[1] Thanos, J. M., Campbell, O. C., Cowan, M. N., Bruch, K. R., Moore, K. A., Ennerfelt, H. E., … & Lukens, J. R. (2025). STING deletion protects against amyloid Ξ²βinduced Alzheimer’s disease pathogenesis. Alzheimer’s & Dementia, 21(5), e70305.
[2] Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018). Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 4, 575-590.
[3] Yu, C. H., Davidson, S., Harapas, C. R., Hilton, J. B., Mlodzianoski, M. J., Laohamonthonkul, P., … & Masters, S. L. (2020). TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING in ALS. Cell, 183(3), 636-649.
