Plasma ceramide mediates the association of peripheral T cells with Alzheimer’s disease

作者：Yunhong Sun, Lili Xia, Xiao-Fan Xu, Xinyu Wang, Jianhe Guo, Ruijie Cheng, Ning Yang, Lihui Shen, Nian Liu, Xiaoxing Mo, Liegang Liu · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.08.027 · 被引用次数：3 · 研究领域：Sphingolipid Metabolism and Signaling、Neuroinflammation and Neurodegeneration Mechanisms、Alzheimer's disease research and treatments

INTRODUCTION: Neuroinflammation involving peripheral immune cells, particularly T lymphocytes, has been implicated in Alzheimer's disease (AD) progression. Metabolic dysregulation in sphingolipid pathways may influence neuroinflammatory processes in AD pathogenesis. However, the specific roles of T cell subsets and their interactions with metabolic pathways in AD pathogenesis remain unclear. OBJECTIVES: To determine the causal contributions of peripheral T cell subsets to AD risk and investigate whether blood metabolites mediate this association. METHODS: We integrated single-cell RNA sequencing with flow cytometry to identify dynamic alterations in T cell subsets during AD progression. Adoptive transfer experiments in APP/PS1 mice validated the functional roles of specific T cell populations. Two-sample Mendelian randomization (MR) evaluated causal relationships between T cell traits and AD risk, while two-step MR assessed the mediating role of blood metabolites. RESULTS: CD4 effector memory (EM) and CD8 central memory (CM) T cells expanded in AD patients, particularly during mild cognitive impairment. Adoptive transfer of either CD4 EM or CD8 CM T cells into APP/PS1 mice exacerbated cognitive deficits and amyloid-β pathology. MR revealed causal associations of CM CD8br % T cell (OR = 1.22, 95 % CI: 1.07-1.39, P = 0.002) and EM CD4+ % CD4+ (OR = 1.09, 95 % CI: 1.01-1.18, P = 0.027) with AD risk. Elevated plasma ceramide levels were also causally associated with increased AD ...