Targeting demyelination via alpha-secretases promoting sAPP alpha release to enhance remyelination in central nervous system

Remyelination is an endogenous regenerative process of myelin repair in the central nervous system (CNS) with limited efficacy in demyelinating disorders. As strategies enhancing endogenous remyelination become a therapeutic challenge, we have focused our study on alpha-secretase-induced sAPP alpha release, a soluble endogenous protein with neuroprotective and neurotrophic properties. However, the role of sAPP alpha in remyelination is not known. Therefore, we investigated the remyelination potential of alpha-secretase-induced sAPP alpha release following CNS demyelination in mice. Acute demyelination was induced by feeding mice with cuprizone (CPZ) for 5 weeks. To test the protective effect and the remyelination potential of etazolate, an alpha-secretase activator, we designed two treatment protocols. Etazolate was administrated either during the last two weeks or at the end of the CPZ intoxication. In both protocols, etazolate restored the number of myelinated axons in corpus callosum with a corresponding increase in the amount of MBP, one of the major myelin proteins in the brain. We also performed ex vivo studies to decipher etazolate's mechanism of action in a lysolecithin-induced demyelination model using organotypic culture of cerebellar slices. Etazolate treatment was able to i) enhance the release of sAPP alpha in the culture media of demyelinated slices, ii) protect myelinated axons from demyelination, iii) increase the number of mature oligodendrocytes, iv) promote the reappearance of the paired Caspr(+)adjacent to the nodes of Ranvier and v) increase the percentage of myelinated axons with short internodes, an indicator of remyelination. Etazolate failed to promote all the aforementioned effects in the presence of GI254023X, an alpha-secretase inhibitor. Moreover, the protective effects of etazolate in demyelinated slices were mimicked by sAPP alpha treatment in a dose-dependent manner. In conclusion, etazolate-induced sAPP alpha release protects myelinated axons from demyelination while also promoting remyelination. This work, thus, highlights the therapeutic potential of strategies that enhance sAPP alpha release in demyelinating disorders.