D4F HDL-mimetic peptide reverses APOE4-induced brain transcriptomic and lipidomic alterations in humanized mice

The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), significantly increasing risk and contributing to neuroinflammation. ApoE4 exhibits reduced lipidation capacity and impaired lipid transport, which disrupts crucial neuronal maintenance processes. This dysfunction leads to widespread alterations in brain gene expression and lipid metabolism. High-density lipoprotein (HDL)-mimetic peptides, such as 4F, offer a promising therapeutic strategy by potentially restoring lipid homeostasis and mitigating APOE4-driven dysregulation.

To investigate APOE4's impact on brain gene expression and lipid metabolism, and to evaluate the therapeutic potential of 4F, researchers utilized humanized APOE4/4 and APOE3/3 mice. Animals were treated intraperitoneally with the D-enantiomer of 4F (D4F) or vehicle for 12 weeks, starting from 10 to 13 months of age. The primary endpoint involved performing dual-omics analysis to comprehensively assess transcriptomic and lipidomic profiles in the brain tissue, comparing the effects of D4F against vehicle and APOE3/3 controls.

Humanized APOE4/4 mice exhibited widespread transcriptomic and lipidomic alterations in the brain compared to APOE3/3 controls. Specifically, they showed significant downregulation of genes involved in lipid metabolism and synaptic pathways. Lipidomic analysis revealed increased levels of ceramides, sphingomyelins, and cholesteryl esters, alongside decreased diglycerides and triglycerides in APOE4/4 brains. These changes reflect a profound dysregulation of lipid homeostasis and neuronal function associated with the APOE4 genotype. > D4F treatment effectively shifted these relevant gene expression and lipid profiles significantly towards those observed in the healthy APOE3/3 mice, indicating a reversal of APOE4-induced pathology. This suggests D4F can mitigate the molecular mechanisms underlying APOE4-driven dysregulation.