β-分泌酶 1 表达升高通过 PGE2 信号介导阿尔茨海默病中 CD4 T 细胞功能障碍。
Elevated β-secretase 1 expression mediates CD4 T cell dysfunction via PGE2 signalling in Alzheimer's disease.
机构信息
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.
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.
出版信息
Brain Behav Immun. 2021 Nov;98:337-348. doi: 10.1016/j.bbi.2021.08.234. Epub 2021 Sep 6.
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.
在阿尔茨海默病（AD）患者中，循环 CD4 T 细胞功能失调，但潜在的分子机制尚不清楚。在这项研究中，我们证明 AD 患者和 5xFAD 转基因小鼠的 CD4 T 细胞中β-分泌酶 1（BACE1）水平升高。在 CD4 T 细胞中过表达 BACE1 可增强 CD4 T 细胞的活化和 T 细胞依赖性免疫反应。在机制上，BACE1 调节前列腺素 E2（PGE2）合酶-微粒体前列腺素 E 合酶 2（mPGES2）以促进 mPGES2 的成熟和 PGE2 的产生，从而增加 T 细胞受体（TCR）信号转导。此外，外周 PGE2 信号转导拮抗剂的给药部分改善了 5xFAD 小鼠中 CD4 T 细胞的过度活化和 AD 病理。总体而言，我们的结果揭示了 BACE1 在介导 AD 中 CD4 T 细胞功能障碍中的潜在作用。
Zotero 插件