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  2. Elevated β-secretase 1 expression mediates CD4+ T cell dysfunction via PGE2 signalling in Alzheimer's disease

Elevated β-secretase 1 expression mediates CD4+ T cell dysfunction via PGE2 signalling in Alzheimer's disease

  • Brain Behav Immun. 2021 Nov;98:337-348. doi: 10.1016/j.bbi.2021.08.234.
Linbin Dai 1 Qiong Wang 1 Xinyi Lv 1 Feng Gao 1 Zuolong Chen 1 Yong Shen 2
Affiliations

Affiliations

  • 1 Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Centre, CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China.
  • 2 Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Centre, CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China; Centre for Excellence in Brain Sciences and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. Electronic address: yongshen@ustc.edu.cn.
Abstract

Circulating CD4+ T cells are dysfunctional in Alzheimer's disease (AD), however, the underlying molecular mechanisms are not clear. In this study, we demonstrate that CD4+ T cells from AD patients and 5xFAD transgenic mice exhibit elevated levels of β-secretase 1 (BACE1). Overexpression of BACE1 in CD4+ T cells potentiated CD4+ T-cell activation and T-cell-dependent immune responses. Mechanistically, BACE1 modulates prostaglandin E2 (PGE2) synthetase-microsomal prostaglandin E synthase 2 (mPGES2)-to promote mPGES2 maturation and PGE2 production, which increases T-cell receptor (TCR) signalling. Moreover, administration of peripheral PGE2 signalling antagonists partially ameliorates CD4+ T cell overactivation and AD pathology in 5xFAD mice. Overall, our results reveal a potential role for BACE1 in mediating CD4+ T-cell dysfunction in AD.

Keywords

Alzheimer’s disease; CD4(+) T cell; Neuroinflammation; PGE2 signalling; T cell receptor (TCR); β-secretase.

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