C5b-9 terminal complement complex protects oligodendrocytes from death by regulating bad through phosphatidylinositol 3-kinase/Akt pathway

Apoptosis of oligodendrocytes is induced by serum growth factor deprivation . We showed that oligodendrocytes and progenitor cells respond to serum wit hdrawal by a rapid decline of Bcl-2 mRNA expression and caspase-3-dependent apoptotic death. Sublytic assembly of membrane-inserted terminal complemen t complexes consisting of C5b, C6, C7, C8, and C9 proteins (C5b-9) inhibits caspase-3 activation and apoptotic death of oligodendrocytes. In this stud y, we examined an involvement of the mitochondria in oligodendrocyte apopto sis and the role of C5b-9 on this process. Decreased phosphatidylinositol 3 -kinase and Akt activities occurred in association with cytochrome c releas e and caspase-9 activation when cells were placed in defined medium. C5b-9 inhibited the mitochondrial pathway of apoptosis in oligodendrocytes, as sh own by decreased cytochrome c release and inhibition of caspase-9 activatio n. Phosphatidylinositol 3-phosphate kinase and Akt activities were also ind uced by C5b-9, and the phosphatidylinositol 3-phosphate kinase inhibitor LY 294002 reversed the protective effect of C5b-9. Phosphatidylinositol 3-phos phate kinase activity was also responsible for the phosphorylation of Bad a t Ser(112) and Ser(136). This phosphorylation resulted in dissociation of B ad from the Bad/Bcl-x(L) complex in a Gi alpha -dependent manner. The mitoc hondrial pathway of oligodendrocyte apoptosis is, therefore, inhibited by C 5b-9 through post-translational regulation of Bad. This mechanism may be in volved in the promotion of oligodendrocyte survival in inflammatory demyeli nating disorders affecting the CNS.