Anti-apoptotic effect of SERM on the amyloid-β-induced apoptosis in PC12

Research Project

Project/Area Number	16591636
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Single-year Grants
Section	一般
Research Field	Obstetrics and gynecology
Research Institution	Yamagata University
Principal Investigator	TAKAHASHI Kazuhiro Yamagata University, Faculty of Medicine, Assistant, 医学部, 助手 (20292427)
Co-Investigator(Kenkyū-buntansha)	KURACHI Hirohisa Yamagata University, Faculty of Medicine, Professor, 医学部, 教授 (40153366) IGARASHI Hideki Yamagata University, Faculty of Medicine, Assistant, 医学部, 助手 (80333970) ABE Akiko Yamagata University, Faculty of Medicine, Assistant, 医学部, 助手 (30359567)
Project Period (FY)	2004 – 2005
Project Status	Completed (Fiscal Year 2005)
Budget Amount *help	¥3,500,000 (Direct Cost: ¥3,500,000) Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000) Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywords	estrogen / raloxifene / Alzheimer / β-Amyloid / apoptosis / PC12 / Akt / telomerase / 神経細胞 / 黄体ホルモン / 神経突起
Research Abstract	According to the scheduled research program, we obtained the results using rat pheochromocytoma cell line (PC12) and PC12 cells transfected with the full-length human estrogen receptor (ER) alpha gene (PCER). Raloxifene, like 17beta-estradiol (E2), significantly inhibited Amyloid β-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 Amyloid β, 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 kappaB 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.