Authors
Shanshan Huang, Zengyu Zhang, Jiajie Xia, Mengqiu Deng, Fangzheng Chen, Meng Wang, Yuchao Fei, Zhiwen Jiang, Chenyu Lu, Jiayu Fu, Jingchun Guo, Houguang Zhou
Published in
Alzheimer's & dementia : the journal of the Alzheimer's Association. Volume 22. Issue 10. Pages e71896.
Abstract
Metabolic stress increases Alzheimer's disease (AD) risk, but mechanisms linking metabolic dysfunction to neuroimmune dysregulation remain unclear.
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.
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.
ZBP1 may contribute to metabolic stress-induced Treg dysfunction and represent a candidate target to improve Treg-based therapy in HFD-fed AD mice.
PMID:
42814409
Bibliographic data and abstract were imported from PubMed on 18 Oct 2026.
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