An oxidized ribonucleotide 8-oxoGTP drives neuroinflammation and accelerates cognitive decline

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.