Linking oxysterols and different stages of mild cognitive impairment: insights from gut metabolites and N6-methyladenosine

作者：Wenjing Feng, Mengwei Ju, Tao Wang, Shanshan Cui, Kexin Yang, Zhiting Guo, Miao Liu, Jiaxuan Tao, Huiyan Yu, Rong Xiao · 发表于：Alzheimer s Research & Therapy · 年份：2025 · DOI：10.1186/s13195-025-01743-5 · 被引用次数：3 · 研究领域：RNA modifications and cancer、Cholesterol and Lipid Metabolism、Epigenetics and DNA Methylation

BACKGROUND: Oxysterols, gut metabolites, and N6-methyladenosine (m6A) are extensively implicated in the pathogenesis of cognitive dysfunction, while their alterations in different stages of mild cognitive impairment (MCI) have not been elucidated. Therefore, this study was conducted to explore the associations of oxysterols, gut metabolites, and m6A methylation profiles in early MCI (EMCI) and late MCI (LMCI) individuals. METHODS: Liquid chromatography-mass spectrometry, untargeted metabolomic analysis, and m6A mRNA Epitranscriptomic Microarray were used to detect the characteristics of serum oxysterols (n = 35/group), fecal gut metabolites (n = 30/group), and m6A in whole blood (n = 4/group) respectively. The concentration of serum β-amyloid (Aβ) was detected with ELISA (n = 25/group). The gene expression of amyloid precursor protein (APP) and its key enzyme β-secretase (BACE1) in whole blood were measured by quantitative real-time PCR (n = 25/group). RESULTS: EMCIs and LMCIs, especially LMCIs, exhibited poorer performance in almost all global and multidimensional cognitive tests. Serum 27-hydroxycholesterol (27-OHC) and 24S-hydroxycholesterol (24S-OHC) were elevated in EMCI and LMCI groups. Changes in gut metabolites occurred mainly in the EMCI group, in which several gut metabolites, including Procyanidin dimer B7 and Phorbol myristate, were significantly decreased. The m6A methylation landscape of EMCIs and LMCIs obviously differed from Controls. Hypomethylated mRNAs acco...