Both estrogen and raloxifene protect against β-amyloid-induced neurotoxicity in estrogen receptor α-transfected PC12 cells by activation of telornerase activity via Akt cascade

Although estrogen is known to protect against beta-amyloid (Abeta)-induced neurotoxicity, the mechanisms responsible for this effect are only beginning to be elucidated. In addition, the effect of raloxifene on Abeta-induced neurotoxicity remains unknown. Here we investigated whether raloxifene exhibits similar neuro-protective effects to estrogen against Abeta-induced neurotoxicity and the mechanism of the effects of these agents in PC12 cells transfected with the fun-length human estrogen receptor (ER) alpha gene (PCER). Raloxifene, like 17beta-estradiol (E-2), significantly inhibited Abeta-induced apoptosis in PCER cells, but not in a control line of cells transfected with vector DNA alone (PCCON). Since telomerase activity, the level of which is modulated by regulation of telomerase catalytic subunit (TERT) at both the transcriptional and post-transcriptional levels, is known to be involved in suppressing apoptosis in neurons, we examined the effect of E-2 and raloxifene on telomerase activity. Although both E-2 and raloxifene induced telomerase activity in PCER cells, but not in PCCON cells, treated with Abeta, they had no effect on the level of TERT expression. These results suggest that neither E-2 nor raloxifene affects the telomerase activity at the transcriptional level. We therefore studied the mechanism by which E-2 and raloxifene induce the telomerase activity at the post-transcriptional level. Both E-2 and raloxifene induced the phosphorylation of Akt, and pretreatment with a phospbatidylinositol 3-kinase inhibitor, LY294002, attenuated both E-2- and raloxifene-induced activation of the telomerase activity. Moreover, both E-2 and raloxifene induced both the phosphorylation of TERT at a putative Akt phosphorylation site and the association of nuclear factor kappaB with TERT. Our findings suggest that E-2 and raloxifene exert neuroprotective effects by telomerase activation via a post-transcriptional cascade in an experimental model relevant to Alzheimer's disease.