Prevention of β-amyloid degeneration of microglia by erythropoietin depends on Wnt1, the PI 3-K/mTOR pathway, Bad, and Bcl-xL

Central nervous system microglia promote neuronal regeneration and sequester toxic beta-amyloid (A beta) deposition during Alzheimer's disease. We show that the cytokine erythropoietin (EPO) decreases the toxic effect of A beta on microglia in vitro. EPO up-regulates the cysteine-rich glycosylated wingless protein Wnt1 and activates the PI 3-K/Akt1/mTOR/p70S6K pathway. This in turn increases phosphorylation and cytosol trafficking of Bad, reduces the Bad/Bcl-x(L) complex and increases the Bcl-x(L)/Bax complex, thus preventing caspase 1 and caspase 3 activation and apoptosis. Our data may foster development of novel strategies to use cytoprotectants such as EPO for Alzheimer's disease and other degenerative disorders.