biostudies-literatureChung SMinistry of Science, ICT and Future Planning (MSIP)Ministry of Health and Welfare (Ministry of Health, Welfare and Family Affairs)Ministry of Education (Ministry of Education of the Republic of Korea)1936-1951https://www.ebi.ac.uk/biostudies/studies/S-EPMC11447230biostudies-literatureUnknown56(9)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 Experimental & molecular medicineBlockade of STING activation alleviates microglial dysfunction and a broad spectrum of Alzheimer's disease pathologies.PMC114472302020R1A6A3A13070845HU23C1234Chung SJeong JHMook-Jung IKim JILee YHan JWPark JCfalseBlockade of STING activation alleviates microglial dysfunction and a broad spectrum of Alzheimer's disease pathologies.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 2024-01-01T00:00:00Z2024 Sep2025-04-26T20:13:04.004Z2025-04-06T16:25:38.756ZS-EPMC114472303921897710.1038/s12276-024-01295-y