An oxidized ribonucleotide 8-oxoGTP drives neuroinflammation and accelerates cognitive decline
10 affiliations
- 1Department of Basic Innovation Research, Beijing Hospital, National Center or Gerontology; National Clinical Research Center for Gerontology; The Key Laboratory of Geriatrics of NHC; Beijing Key Laboratory of Aging Mechanism and Intervention Research on Aging-Related Diseases; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- 2Chinese Institute for Immunology, Chinese Institutes for Medical Research, Beijing, China.
- 3School of Basic Medicine, Capital Medical University, Beijing, China.
- 4Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
- 5The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
- 6Department of Pulmonary and Critical Care Medicine, Peking University Shougang Hospital, Beijing, China.
- 7Department of Clinical laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
- 8Department of Pathology, Beijing Hospital, National Center of Gerontology, Beijing, China.
- 9Department of Neurology, Beijing Hospital, National Center of Gerontology; Institute of geriatric medicine, Chinese academy of medical sciences, Beijing, China.
- 10School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Abstract
Oxidative stress is a hallmark of aging and a key driver of neurodegenerative diseases. While much attention has been given to oxidative damage of macromolecules, the functional consequences of oxidizing the abundant nucleotide triphosphate (NTP) pool remain largely unknown. Here, we identify oxidized GTP (8-oxoGTP)-a major product of NTP oxidation-not as a mere marker of damage, but as an endogenous signaling molecule that drives microglial activation and neuroinflammation. 8-oxoGTP accumulated in the aging mouse brain, and its elevation was sufficient to induce synaptic dysfunction, tau hyperphosphorylation, neuronal loss, and cognitive decline. Mechanistically, 8-oxoGTP functioned as a potent activator of heterotrimeric G proteins, binding more strongly to Gα subunits than GTP itself, triggering Src kinase/MAPK/Akt/NF-κB signaling in microglia, leading to pro-inflammatory cytokine production, reactive oxygen species generation, and neurotoxicity. Pharmacological inhibition of Src family kinases rescued the neuroinflammatory and cognitive phenotypes induced by 8-oxoGTP. Our findings reveal a previously unrecognized mechanism linking nucleotide oxidation to age-associated neurodegenerative processes.
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BibTeX
@article{li2026oxidized,
title = {{An oxidized ribonucleotide 8-oxoGTP drives neuroinflammation and accelerates cognitive decline}},
author = {Jin Li and Zhen-He Wang and Jia-Xin Pan and Zhe-Li Jiang and Rui Li and Xu-Fan Gao and Gang Sheng and Zi-Hui Wang and Ya-Qing Ma and Zheng-Lu Wang and Ting Wang and Ran Huan and Lv-Tao Zeng and Wei Zhang and Da-Peng Dai and Ju Cui and Xiao-Yang Zhou and Li-Qun Zhang and Wen Su and Hai-Bo Chen and Guo-Xin Hu and Ruo-Mei Qi and Jian-Ping Cai},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aee0110},
url = {https://www.science.org/doi/abs/10.1126/sciadv.aee0110},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - An oxidized ribonucleotide 8-oxoGTP drives neuroinflammation and accelerates cognitive decline
AU - Jin Li
AU - Zhen-He Wang
AU - Jia-Xin Pan
AU - Zhe-Li Jiang
AU - Rui Li
AU - Xu-Fan Gao
AU - Gang Sheng
AU - Zi-Hui Wang
AU - Ya-Qing Ma
AU - Zheng-Lu Wang
AU - Ting Wang
AU - Ran Huan
AU - Lv-Tao Zeng
AU - Wei Zhang
AU - Da-Peng Dai
AU - Ju Cui
AU - Xiao-Yang Zhou
AU - Li-Qun Zhang
AU - Wen Su
AU - Hai-Bo Chen
AU - Guo-Xin Hu
AU - Ruo-Mei Qi
AU - Jian-Ping Cai
PY - 2026
DA - 2026/10/28
JO - Science Advances
DO - 10.1126/sciadv.aee0110
UR - https://www.science.org/doi/abs/10.1126/sciadv.aee0110
AB - Oxidative stress is a hallmark of aging and a key driver of neurodegenerative diseases. While much attention has been given to oxidative damage of macromolecules, the functional consequences of oxidizing the abundant nucleotide triphosphate (NTP) pool remain largely unknown. Here, we identify oxidized GTP (8-oxoGTP)-a major product of NTP oxidation-not as a mere marker of damage, but as an endogenous signaling molecule that drives microglial activation and neuroinflammation. 8-oxoGTP accumulated in the aging mouse brain, and its elevation was sufficient to induce synaptic dysfunction, tau hyperphosphorylation, neuronal loss, and cognitive decline. Mechanistically, 8-oxoGTP functioned as a potent activator of heterotrimeric G proteins, binding more strongly to Gα subunits than GTP itself, triggering Src kinase/MAPK/Akt/NF-κB signaling in microglia, leading to pro-inflammatory cytokine production, reactive oxygen species generation, and neurotoxicity. Pharmacological inhibition of Src family kinases rescued the neuroinflammatory and cognitive phenotypes induced by 8-oxoGTP. Our findings reveal a previously unrecognized mechanism linking nucleotide oxidation to age-associated neurodegenerative processes.
SN - 2375-2548
ER -