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

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.