Ogg1 regulates context-dependent glial states in Alzheimer's disease

Oxidative DNA damage is an early hallmark of Alzheimer's disease (AD), but whether Ogg1, a key enzyme in oxidative DNA repair, contributes to disease pathogenesis remains unclear. Here, we show that Ogg1 exerts opposing effects under physiological and disease conditions. Ogg1 deficiency impaired memory and induced glial transcriptional alterations under physiological conditions, whereas in APP/PS1 mice it improved memory, reduced amyloid burden and attenuated AD-associated glial remodeling. These effects occurred without changes in global 8-oxo-dG levels and were accompanied by changes in chromatin accessibility and gene expression, supporting a non-canonical role for Ogg1 in transcriptional regulation. Single-nucleus transcriptomics revealed strong transcriptional responses to Ogg1 deficiency across all major glial cell types and showed that Ogg1-dependent glial transcriptional programs are strongly conserved in human AD. These findings identify Ogg1 as a context-dependent regulator of glial cell states and reveal an unexpected role in AD-associated glial remodeling.