An Apolipoprotein E-Mimetic Stimulates Axonal Regeneration and Remyelination after Peripheral Nerve Injury

Abstract

Elevated apolipoprotein E (apoE) synthesis within crushed sciatic nerves advocates that apoE could benefit axonal repair and reconstruction of axonal and myelin membranes. We created an apoE-mimetic peptide, COG112 (acetyl-RQIKIWFQNRRMK-WKKCLRVRLASHLRKLRKRLL-amide), and found that postinjury treatment with COG112 significantly improved recovery of motor and sensory function following sciatic nerve crush in C57BL/6 mice. Morphometric analysis of injured sciatic nerves revealed that COG112 promoted axonal regrowth after 2 weeks of treatment. More strikingly, the thickness of myelin sheaths was increased by COG112 treatment. Consistent with these histological findings, COG112 potently elevated growth associated protein 43 (GAP-43) and peripheral myelin protein zero (P0), which are markers of axon regeneration and remyelination, respectively. Electron microscopic examination further suggested that the apoE-mimetic COG112 may increase clearance of myelin debris. Schwann cell uptake of cholesterol-containing low-density lipoprotein particles was selectively enhanced by COG112 treatment in a Schwann cell line S16. Moreover, COG112 significantly promoted axon elongation in primary dorsal root ganglion cultures from rat pups. Considering that cholesterol and lipids are needed for reconstructing myelin sheaths and axon extension, these data support a hypothesis where supplementation with exogenous apoE-mimetics such as COG112 may be a promising strategy for restoring lost functional and structural elements following nerve injury.

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

“…Previous studies showed that the apoE-mimetic peptides, which were derived from the receptor-binding domain of apoE protein, (i.e., apoE133–149), could bind apoE receptors to simulate the bioactivities of the holo-protein (Li et al, 2006; Singh et al, 2008; Li et al, 2010). We first tested whether administration of apoE peptides could decrease the permeability of BSCB in apoE −/− mice following SCI.…”

Attenuation of Acute Rat Renal Allograft Rejection by Apolipoprotein E-Mimetic Peptide

“…3,5,8,9,[15][16][17][18][19][20][21][22][23][24]39,40 In the present study, we are the first to demonstrate a protective role of ApoE (133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144)(145)(146)(147)(148)(149) in experimental acute kidney graft rejection. This effect was associated with a reduced influx of α/β TCR-expressing cells and CD8 pos cells as well as diminished expression of GrB and decreased levels of active caspase-3.…”

“…15 Furthermore, ApoE (133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144)(145)(146)(147)(148)(149) can directly compete with the binding of ApoE to cell surface receptors. 15 Protective effects of exogenous ApoE and ApoE (133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144)(145)(146)(147)(148)(149) were found in the context of several inflammatory disorders, [15][16][17][18][19][20][21][22][23][24] but their effect on the pathogenesis of acute organ rejection is still unknown.…”

Growth/differentiation factor-15 and its role in peripheral nervous system lesion and regeneration

“…Lipid binding proteins, such as Apolipoproteins D and E (ApoD, ApoE), accumulate in the distal nerve portion after injury. ApoD is mainly expressed by endoneural fibroblasts, while ApoE is primarily produced by infiltrating macrophages (Li et al, 2010;Spreyer et al, 1990;Stoll and Muller, 1986).…”