Brain, Behavior, and Immunity | September 6, 2021

Dai L, Wang Q, Lv X, Gao F, Chen Z and Shen Y

Brain, behavior, and immunity. 2021;98:337-348

https://doi.org/10.1016/j.bbi.2021.08.234

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.