Tet2 deficiency orchestrates Alzheimer's pathogenesis through oxidative mtDNA-driven cGAS-STING activation.

Emerging evidence underscores the pivotal role of Ten-eleven translocation 2 (Tet2), as an epigenetic regulator with neuroprotective functions, yet its temporal dynamics and pathogenic contributions to Alzheimer’s disease (AD) remain poorly understood. By integrating human longitudinal cohort data with experimental models, we demonstrated that Tet2 deficiency accelerated AD‑like neurodegeneration through oxidative stress-dependent cGAS-STING activation. Clinically, Tet2 loss-of-function carriers among Aβ-positive individuals exhibited significantly accelerated cognitive decline. In mice, Tet2 expression decreased with age and in late‑stage AD models, and constitutive Tet2‑mutant (Tet2mut) mice recapitulated AD-like behaviors and pathology by exacerbating neuroinflammation and impairing neurogenesis and synaptic plasticity. Crucially, Tet2 deficiency induced mitochondrial dysmorphology and heightened oxidative stress in the hippocampus, culminating in DNA damage and robust cGAS-STING activation. Mechanistically, integrative epigenomic analyses further revealed that Tet2 deficiency was associated with hypermethylation of antioxidant gene networks, thereby exacerbating oxidative stress and mitochondrial injury. Notably, antioxidant treatment with N-acetylcysteine (NAC) effectively alleviated oxidative damage, restored mitochondrial function and suppressed cGAS-STING signaling in Tet2-silenced microglia. In vivo, NAC administration in Tet2mut mice improved cognitive performance and synaptic plasticity while reducing neuroinflammation and neuronal loss through inhibition of cGAS-STING signaling. These findings delineate a previously unrecognized epigenetic-immune axis in AD, highlighting Tet2 enhancement and ROS modulation as promising therapeutic strategies.