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.

循环 CD4 ⁺ T 细胞在阿尔茨海默病 (AD) 中功能失调，然而，潜在的分子机制尚不清楚。在这项研究中，我们证明来自 AD 患者和 5xFAD 转基因小鼠的 CD4 ⁺ T 细胞表现出升高的 β-分泌酶 1 (BACE1) 水平。^{CD4 +} T 细胞中 BACE1 的过表达增强了 CD4 ⁺ T 细胞活化和 T 细胞依赖性免疫反应。从机制上讲，BACE1 调节前列腺素 E2 (PGE2) 合成酶——微粒体前列腺素 E 合成酶 2 (mPGES2)——以促进 mPGES2 成熟和 PGE2 产生，从而增加 T 细胞受体 (TCR) 信号传导。此外，外周 PGE2 信号传导拮抗剂的施用可部分改善 CD4 ⁺5xFAD 小鼠的 T 细胞过度激活和 AD 病理学。^{总体而言，我们的结果揭示了 BACE1 在介导 AD 中 CD4 +} T 细胞功能障碍的潜在作用。