ZBP1‐mediated Treg cell dysfunction exacerbates neuroimmune dysregulation in Alzheimer's disease under metabolic stress

Abstract INTRODUCTION Metabolic stress increases Alzheimer's disease (AD) risk, but mechanisms linking metabolic dysfunction to neuroimmune dysregulation remain unclear. METHODS We assessed cognition in community‐dwelling participants and used high‐fat diet (HFD)‐fed 5xFAD mice, high glucose and high palmitate (HGHP)‐treated regulatory T cell (Treg) co‐cultures, and adoptive Treg transfer to evaluate metabolic stress‐associated neuroimmune dysfunction. Flow cytometry, RNA sequencing, positron emission tomography computed tomography, and electrophysiology assessed Treg function, AD pathology, cerebral metabolism, and synaptic plasticity. RESULTS Metabolic stress impaired Treg stability and function, accompanied by increased Z‐DNA‐binding protein 1 (ZBP1) expression and activation of apoptotic and necroptotic signaling. Treg dysfunction was associated with enhanced glial activation and neuronal injury. Under HGHP stress, ZBP1‐deficient Tregs showed improved survival and stronger immunosuppressive activity, more effectively limiting glial activation and preserving neuronal integrity. In vivo, ZBP1‐deficient Treg transfer conferred greater neuroprotection than wild‐type Treg transfer in HFD‐fed AD mice. DISCUSSION ZBP1 may contribute to metabolic stress–induced Treg dysfunction and represent a candidate target to improve Treg‐based therapy in HFD‐fed AD mice.