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

Elevation of oxidized GTP, 8-oxoGTP, in aging mouse brain is sufficient to induce synaptic dysfunction, tau hyperphosphorylation, neuronal loss, and cognitive decline.

• Why it matters: Oxidative stress is linked to aging and neurodegeneration, but how oxidizing the nucleotide triphosphate pool functionally contributes to disease has been unclear.
• What they did: The study identified 8-oxoGTP as an endogenous signaling molecule, showing it accumulates in aging mouse brain and activates microglial heterotrimeric G proteins to trigger Src kinase/MAPK/Akt/NF-κB signaling.
• The result: Src family kinase inhibition rescued the neuroinflammatory and cognitive phenotypes induced by 8-oxoGTP, implying nucleotide oxidation can directly drive age-associated neurodegenerative processes.