Abstract Background and aims Tumor necrosis factor receptor-associated factor 3 (TRAF3) is an adaptor in immune signalling linked to central nervous system inflammation, but its contribution to Alzheimer’s disease (AD) pathology remains unclear. We investigated whether TRAF3 knockdown can mitigate neuroinflammation and improve pathological and cognitive outcomes in an AD model. Methods APP/PS1 transgenic mice and primary neuronal cultures received adeno-associated virus (AAV)–shRNA to silence TRAF3 (vs control shRNA). Cognition was assessed by Morris water maze and novel object recognition. Amyloid-β burden, phosphorylated tau, and glial activation were quantified by immunohistochemistry and ELISA. NF-κB/MAPK and interferon regulatory factor (IRF) pathway signalling was evaluated by Western blotting and qPCR. Results TRAF3 knockdown reduced microglial activation and pro-inflammatory cytokines, decreased amyloid plaque load and phosphorylated tau (p0.05), and improved spatial learning and memory. Mechanistic analyses suggest dampening of TAK1-dependent MAPK/NF-κB signalling with modulation of IRF-mediated interferon responses, attenuating inflammatory gene programmes in vivo and in vitro. Ongoing work is testing cell-type specificity and durability of benefit to inform therapeutic translation. Conflict of interest Yingao Fan ,Xiaolei Zhu: nothing to disclose.
Fan et al. (2026) studied this question.