α-Tocopherol impairs 7-ketocholesterol-induced caspase-3-dependent apoptosis involving GSK-3 activation and Mcl-1 degradation on 158N murine oligodendrocytes

In important and severe neurodegenerative pathologies, 7-ketocholesterol, mainly resulting from cholesterol autoxidation, may contribute to dys- or demyelination processes. On various cell types, 7-ketocholesterol has often been shown to induce a complex mode of cell death by apoptosis associated with phospholipidosis. On 158N murine oligodendrocytes treated with 7-ketocholesterol (20 mu g/mL corresponding to 50 mu M, 24-48 h), the induction of a mode of cell death by apoptosis characterised by the occurrence of cells with condensed and/or fragmented nuclei, caspase activation (including caspase-3) and internucleosomal DNA fragmentation was observed. It was associated with a loss of transmembrane mitochondrial potential (Delta Psi m) measured with JC-1, with a dephosphorylation of Akt and GSK3 (especially GSK3 beta), and with degradation of Mcl-1. With alpha-tocopherol (400 mu M), which was capable of counteracting 7-ketocholesterol-induced apoptosis, Akt and GSK3 beta dephosphorylation were inhibited as well as Mcl-1 degradation. These data underline that the potential protective effects of alpha-tocopherol against 7-ketocholesterol-induced apoptosis do not depend on the cell line considered, and that the cascade of events (Akt/GSK3 beta/Mcl-1) constitutes a link between 7-ketocholesterol-induced cytoplasmic membrane dysfunctions and mitochondrial depolarisation leading to apoptosis. (C) 2011 Elsevier Ireland Ltd. All rights reserved.