Reimund, M. | Search bioRxiv

bioRxiv2026

The ApoC2 mimetic peptide D6PV enhances remyelination by stimulating oxidative phosphorylation in oligodendrocytes

Failure of remyelination drives neurodegeneration in demyelinating disorders such as multiple sclerosis (MS), with disrupted lipid handling and metabolic stress in oligodendrocyte precursor cells (OPCs) posing major barriers to repair. Here, we identify the dual ApoC-II mimetic-ApoC-III antagonist peptide D6PV as a metabolic modulator that directly enhances OPC differentiation and myelin repair. Across ex vivo and in vivo models of chemically induced demyelination, D6PV promotes oligodendrocyte maturation and restores myelin integrity independently of lipoprotein hydrolysis or modulation of lipid droplet-containing phagocytes. Guided by transcriptomics analyses, we find that D6PV stimulates mitochondrial oxidative phosphorylation and fatty acid {beta}-oxidation, while suppressing inflammatory transcriptional programs, thereby driving OPCs toward a myelinating phenotype. Notably, D6PV does not alter peripheral immune composition or autoimmune-driven pathology in the experimental autoimmune encephalomyelitis model, indicating a central nervous system (CNS) cell-autonomous effect. These findings reveal a metabolism-linked pathway for remyelination and position D6PV as a promising therapeutic strategy to enhance CNS repair in demyelinating diseases.

neuroscience↗

bioRxiv2023

Structural flexibility of apolipoprotein E-derived arginine-rich peptides improves their cell penetration capability

Amphipathic arginine-rich peptide, A2-17, exhibits moderate perturbation of lipid membranes and the highest cell penetration among its structural isomers. We investigated the direct cell-membrane penetration mechanism of the A2-17 peptide. We designed structurally constrained versions of A2-17, stapled (StpA2-17) and stitched (StchA2-17), whose -helical conformations were stabilized by chemical crosslinking. Circular dichroism confirmed that StpA2-17 and StchA2-17 had higher -helix content than A2-17 in aqueous solution. Upon liposome binding, only A2-17 exhibited a coil-to-helix transition. Confocal microscopy revealed that A2-17 had higher cell penetration efficiency than StpA2-17 in HeLa cells. Partitioning into lipid membranes was more prominent for StchA2-17 than for A2-17 or StpA2-17; StchA2-17 remained on the cell membrane without cell penetration. Tryptophan fluorescence analysis suggested that A2-17 and its analogs had similar membrane-insertion positions between the interface and hydrophobic core. Atomic force microscopy demonstrated that A2-17 reduced the mechanical rigidity of liposomes to a greater extent than StpA2-17 and StchA2-17. Finally, electrophysiological analysis showed that A2-17 induced a higher charge influx through transient pores in a planer lipid bilayer than StpA2-17 and StchA2-17. These findings indicate that structural flexibility, which enables diverse conformations of A2-17, leads to a membrane perturbation mode that contributes to cell membrane penetration.

biophysics↗