Low sulfated heparins target multiple proteins for central nervous system repair. Issue 4 (26th December 2018)

• Record Type: Journal Article
• Authors: McCanney, George A.; McGrath, Michael A.; Otto, Thomas D.; Burchmore, Richard; Yates, Edwin A.; Bavington, Charles D.; Willison, Hugh J.; Turnbull, Jeremy E.; Barnett, Susan C.
• Is Part Of: Glia. Volume 67:Issue 4(2019)
• Page Start: 668
• Page End: 687
• Publication Date: 2018-12-26
• Subjects: amyloid‐β -- heparan sulfates -- myelination -- neurite outgrowth; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.23562
• Languages: English
• ISSNs: 0894-1491

Abstract

Abstract: The lack of endogenous repair following spinal cord injury (SCI) accounts for the frequent permanent deficits for which effective treatments are absent. Previously, we demonstrated that low sulfated modified heparin mimetics (LS‐mHeps) attenuate astrocytosis, suggesting they may represent a novel therapeutic approach. mHeps are glycomolecules with structural similarities to resident heparan sulfates (HS), which modulate cell signaling by both sequestering ligands, and acting as cofactors in the formation of ligand–receptor complexes. To explore whether mHeps can affect the myelination and neurite outgrowth necessary for repair after SCI, we created lesioned or demyelinated neural cell co‐cultures and exposed them with a panel of mHeps with varying degrees and positions of their sulfate moieties. LS‐mHep7 enhanced neurite outgrowth and myelination, whereas highly sulfated mHeps (HS‐mHeps) had attenuating effects. LS‐mHeps had no effects on myelination or neurite extension in developing, uninjured myelinating cultures, suggesting they might exert their proregenerating effects by modulating or sequestering inhibitory factors secreted after injury. To investigate this, we examined conditioned media from cultures using chemokine arrays and conducted an unbiased proteomics approach by applying TMT‐LC/MS to mHep7 affinity purified conditioned media from these cultures. Multiple protein factors reported to play a role in damage or repair mechanisms were identified, including amyloid betaA4. Amyloid beta peptide (1–42) was validated as an important candidate by treating myelination cultures and shown to inhibit myelination. Thus, we propose that LS‐mHeps exert multiple beneficial effects on mechanisms supporting enhanced repair, and represent novel candidates as therapeutics for CNS damage. Main Points: Heparin binding‐factors are secreted after CNS injury that affect repair. Low sulphated modified heparin mimetics exert beneficial effects on CNS repair. Using TMT/LC–MS we identified amyloid betaA4 as a secreted demyelination factor.