한빛사논문
Sunwoo Chung 1,2, June-Hyun Jeong 1,2, Jong-Chan Park 3, Jong Won Han 1,2, Yeajina Lee 2,4, Jong-Il Kim 2,4 and Inhee Mook-Jung 1,2,*
1Convergence Dementia Research Center, College of Medicine, Seoul National University, 03080 Seoul, Korea.
2Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, 03080 Seoul, Korea.
3Department of Biophysics & Institute of Quantum Biophysics, Sungkyunkwan University, 16419 Gyeonggi-do, Korea.
4Genomic Medicine Institute, Medical Research Center, Seoul National University, 03080 Seoul, Korea.
*Corresponding author: correspondence to Inhee Mook-Jung
Abstract
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 AppNL-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.
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