Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
ZBP1-mediated Treg cell dysfunction exacerbates neuroimmune dysregulation in Alzheimer's disease under metabolic stress.
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Huang Shanshan, Zhang Zengyu, Xia Jiajie, Deng Mengqiu, Chen Fangzheng, Wang Meng, Fei Yuchao, Jiang Zhiwen, Lu Chenyu, Fu Jiayu, Guo Jingchun, Zhou Houguang
Аннотация
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.
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.