Blockade of STING activation alleviates microglial dysfunction and a broad spectrum of Alzheimer’s disease pathologies

• Published in: Experimental & molecular medicine Vol. 56; no. 9; pp. 1936 - 1951
• Main Authors: Chung, Sunwoo, Jeong, June-Hyun, Park, Jong-Chan, Han, Jong Won, Lee, Yeajina, Kim, Jong-Il, Mook-Jung, Inhee
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2024; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 13/100; 14/19; 45/91; 631/378/1689/1283; 631/378/371; 64/110; 82/51; 82/80; Alzheimer Disease - etiology; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Apolipoprotein E; Artificial intelligence; Biomedical and Life Sciences; Biomedicine; Brain; Brain injury; Cytoplasm; Dementia disorders; Disease Models, Animal; Gliosis; Humans; Immune response; Immunological memory; Inflammation; Medical Biochemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Memory; Mice; Mice, Transgenic; Microglia; Microglia - metabolism; Microglia - pathology; Mitochondrial DNA; Molecular Medicine; Neurodegeneration; Neurodegenerative diseases; Neuronal-glial interactions; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Phosphorylation; Proteins; Risk factors; Signal Transduction; Stem Cells; Synapses; Tau protein; Therapeutic targets; Transcriptomes; β-Amyloid; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-024-01295-y

Abnormal glial activation promotes neurodegeneration in Alzheimer’s disease (AD), the most common cause of dementia. Stimulation of the cGAS-STING pathway induces microglial dysfunction and sterile inflammation, which exacerbates AD. We showed that inhibiting STING activation can control microglia and ameliorate a wide spectrum of AD symptoms. The cGAS-STING pathway is required for the detection of ectopic DNA and the subsequent immune response. Amyloid-β (Aβ) and tau induce mitochondrial stress, which causes DNA to be released into the cytoplasm of microglia. cGAS and STING are highly expressed in Aβ plaque-associated microglia, and neuronal STING is upregulated in the brains of AD model animals. The presence of the APOE ε4 allele, an AD risk factor, also upregulated both proteins. STING activation was necessary for microglial NLRP3 activation, proinflammatory responses, and type-I-interferon responses. Pharmacological STING inhibition reduced a wide range of AD pathogenic features in App NL-G-F /hTau double-knock-in mice. An unanticipated transcriptome shift in microglia reduced gliosis and cerebral inflammation. Significant reductions in the Aβ load, tau phosphorylation, and microglial synapse engulfment prevented memory loss. To summarize, our study describes the pathogenic mechanism of STING activation as well as its potential as a therapeutic target in AD. STING inhibition mitigates neurodegeneration in Alzheimer’s disease In illnesses like Alzheimer’s that cause brain deterioration, the brain’s defense cells, known as microglia, overreact due to harmful proteins, causing brain damage and memory loss. This research aimed to understand how microglia change in Alzheimer’s and find ways to stop their damaging effects. Using mice with Alzheimer’s, they checked if blocking specific immune pathway could fix microglia dysfunction and Alzheimer’s disease pathologies. They discovered that blocking STING, a crucial part of this pathway, reduced microglia dysfunction brain inflammation, decreased the buildup of Alzheimer’s-related proteins, and improved memory in mice. By blocking the STING activation, the study showed a decrease in damaging brain inflammation and improvements in memory function, suggesting a promising strategy for treating Alzheimer’s. Researchers conclude that targeting the STING could offer a new way to fight Alzheimer’s by reducing inflammation and protecting brain health. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.