ADAM10 suppresses demyelination and reduces seizure susceptibility in cuprizone-induced demyelination model.

The metalloproteinase ADAM10 is the most important amyloid precursor protein (APP) α-secretase, preventing the deposit of neurotoxic amyloid β (Aβ) peptide and generating a soluble APP fragment (sAPP α) with neurotrophic functions. Recent studies have suggested that ADAM10 also play a role in the pathogenesis of inflammatory CNS diseases, such as multiple sclerosis (MS). Demyelination is the hallmarks of MS but the mechanisms involved remain unclear. Here in this study, we examined the role that ADAM10 might play in the cuprizone-induced demyelination model. Our results demonstrated that ADAM10 expression and sAPP α production were significantly reduced in the corpus callosum in response to cuprizone treatment. Overexpression of ADAM10 increased sAPP α production and suppressed demyelination as well as neuroinflammation and oxidative stress in cuprizone-induced demyelination model. Pharmacological inhibition of ADAM10 activity, however, abrogates the protective effect of ADAM10 against demyelination, neuroinflammation and oxidative stress. It has been reported that CNS demyelination may induce seizure activity. Here, we found that overexpression of ADAM10 reduced seizure susceptibility in cuprizone-induced demyelination model, suggesting that ADAM10-derived sAPP α suppresses demyelination and reduces seizure susceptibility via ameliorating neuroinflammation and oxidative stress in cuprizone-induced demyelination model. [Display omitted] • ADAM10 expression is reduced in cupizone-induced demyelination. • ADAM10 protects against cupizone-induced myelin structural protein loss. • ADAM10 suppresses CPZ-induced mature oligodendrocytes loss and oligodendrocyte progenitor cells proliferation. • Inhibition of ADAM10 abrogates the protective effect of ADAM10 against demyelination and oxidative stress. • ADAM10 suppresses CPZ-induced seizure susceptibility. [ABSTRACT FROM AUTHOR]