HDL-mimetic peptide treatment reverses APOE4-induced transcriptomic and lipidomic alterations in the brain of humanized APOE mice

INTRODUCTION: The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). APOE4 has reduced lipidation capacity and impaired lipid transport, disrupting neuronal maintenance. The high-density lipoprotein (HDL)-mimetic peptide 4F offers a potential therapeutic strategy. METHODS: To investigate how APOE4 alters brain gene expression and lipid metabolism and to evaluate the therapeutic potential of 4F, we performed dual-omics analysis in APOE4/4 (E4/4) and APOE3/3 (E3/3) mice treated intraperitoneally with D-enantiomer of 4F (D4F) or vehicle for 12 weeks to 13 months of age. RESULTS: APOE4/4 mice showed widespread transcriptomic and lipidomic alterations, including downregulation of lipid metabolism and synaptic pathways, increased ceramides, sphingomyelins, and cholesteryl esters, and decreased triglycerides and diglycerides. D4F treatment restored gene expression and lipid profiles toward APOE3/3 levels. DISCUSSION: These findings reveal molecular mechanisms underlying APOE4-driven dysregulation and support the therapeutic potential of HDL-mimetic peptides to mitigate APOE4-associated alterations in AD.