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Department of Obstetrics and Gynecology, Yamagata University, School of Medicine, 2-2-2 Iidanishi, Yamagata 990-9585, Japan
¹ Division of Nursing, Yamagata University, School of Medicine, 2-2-2 Iidanishi, Yamagata 990-9585, Japan

(Requests for offprints should be addressed to M Ohmichi; Email: masa{at}med.id.yamagata-u.ac.jp)

Although estrogen is known to protect against ß-amyloid (Aß)-induced neurotoxicity, the mechanisms responsible for this effect are only beginning to be elucidated. In addition, the effect of raloxifene on Aß-induced neuro-toxicity remains unknown. Here we investigated whether raloxifene exhibits similar neuro-protective effects to estrogen against Aß-induced neurotoxicity and the mechanism of the effects of these agents in PC12 cells transfected with the full-length human estrogen receptor (ER) gene (PCER). Raloxifene, like 17ß-estradiol (E₂), significantly inhibited Aß-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 E₂ and raloxifene on telomerase activity. Although both E₂ and raloxifene induced telomerase activity in PCER cells, but not in PCCON cells, treated with Aß, they had no effect on the level of TERT expression. These results suggest that neither E₂ nor raloxifene affects the telomerase activity at the transcriptional level. We therefore studied the mechanism by which E₂ and raloxifene induce the telomerase activity at the post-transcriptional level. Both E₂ and raloxifene induced the phosphorylation of Akt, and pre-treatment with a phosphatidylinositol 3-kinase inhibitor, LY294002, attenuated both E₂^– and raloxifene-induced activation of the telomerase activity. Moreover, both E₂ and raloxifene induced both the phosphorylation of TERT at a putative Akt phosphorylation site and the association of nuclear factor B with TERT. Our findings suggest that and raloxifene exert neuroprotective effects by E₂ telomerase activation via a post-transcriptional cascade in an experimental model relevant to Alzheimer’s disease.

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