文献类型：期刊文献

英文题名：APOE4-driven lipid metabolic dysregulation in Alzheimer's disease: Multi-pathway mechanisms and therapeutic perspectives

作者：Zhang, Wen-Xuan[1];Yang, Yi-Liang[1,2];Yu, Jia-Xin[1];Jia, Li-Hong[1,2];Huang, Han-Chang[1,2]

第一作者：Zhang, Wen-Xuan

通讯作者：Huang, HC[1]

机构：[1]Beijing Union Univ, Beijing Key Lab Bioact Subst & Funct Foods, Beijing 100023, Peoples R China;[2]Beijing Union Univ, Key Lab Nat Prod Dev & Innovat Drug Res, Beijing 100023, Peoples R China

第一机构：北京联合大学应用文理学院|北京联合大学生物化学工程学院

通讯机构：[1]corresponding author), Beijing Union Univ, Beijing Key Lab Bioact Subst & Funct Foods, Beijing 100023, Peoples R China.|[114172]北京联合大学应用文理学院;[11417]北京联合大学;[1141726]北京联合大学生物化学工程学院;

年份：2025

卷号：778

外文期刊名：BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

收录：;Scopus(收录号：2-s2.0-105010556280);WOS:【SCI-EXPANDED(收录号:WOS:001539000700002)】；

基金：This study was supported by the Academic Research Projects of Beijing Union University, China (ZKZD202304 and ZK70202101) .

语种：英文

外文关键词：Alzheimer's disease; APOE4; cholesterol; Lipid metabolism; Blood-brain barrier

摘要：Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by senile plaques deposition and hyperphosphorylated Tau. As the primary genetic risk factor for late-onset AD (LOAD), Apolipoprotein E4 (APOE4) might drive the core pathological progression of this disease through lipid metabolism dysregulation. Due to its relatively lower lipid-binding efficiency compared to APOE3, APOE4 impairs cholesterol efflux, leading to lipid droplet (LD) accumulation and lysosomal dysfunction in neurons and glial cells. APOE4 also disrupts the microglia TREM2-APOE signaling axis asnd exacerbates neuroinflammation by activating the TLR4/ NF-kappa B pathway. In oligodendrocytes, APOE4 induces dysregulation of the LXR(3/ABCA1 pathway and results in sphingolipid metabolism imbalance and demyelination. Furthermore, APOE4 compromises the integrity of blood-brain barrier and activates the CypA-MMP9 pathway, facilitating the infiltration of peripheral inflammatory cytokine and cerebrovascular pathology. This article summarized the evidence that APOE4 affects lipid metabolism through various pathways and proposed the potential therapeutic strategies to alleviate the progression of AD.