Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling.
Beta-site APP-cleaving enzyme 1 (BACE1) expression is elevated in the brains of Alzheimer's disease (AD) patients and in aged-animal models. Because both AD and aging are associated with disrupted calcium homeostasis, we investigated the role of nuclear factor of activated T cells (NFAT) - a transcription factor regulated by the calcium- and calmodulin-dependent phosphatase calcineurin - in BACE1 expression. BACE1 expression was stimulated by a calcium ionophore in primary cortical cultures, and by SH-SY5Y neuroblastoma cells, which was both blocked by pretreatment with either cyclosporin A, an inhibitor of calcineurin, or ethyleneglycotetraacetic acid, a calcium chelator. Gel shift assays revealed direct binding of NFAT1 to specific DNA sequences within the BACE1 gene promoter region. Treatment with amyloid beta (Abeta), one of the major factors in AD pathogenesis, stimulated activation and nuclear translocation of NFAT1 following up-regulation of BACE1 expression. In addition, primary cortical cultures from Tg2576 mouse brains generated more Abeta by ionophore stimulation, which was reversed by cyclosporin A treatment. Furthermore, NFAT1 activation was observed in Tg2576 mouse brains. These results suggest that calcium ionophore- or Abeta-induced increases in intracellular calcium concentration stimulate BACE1 expression, resulting in accelerated Abeta generation, and that this process is mediated through the calcineurin-NFAT1 signaling pathway. This process may play a significant role in the pathogenesis of AD and aging.
Cho
Hyun Jin
HJ
Department of Biochemistry and Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
Jin
Seok Min
SM
Youn
Hong Deuk
HD
Huh
Kyoon
K
Mook-Jung
Inhee
I
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000375:Aging / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004533:Egtazic Acid / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007476:Ionophores; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D009447:Neuroblastoma; D011401:Promoter Regions, Genetic; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D065095:Calcineurin Inhibitors; D002614:Chelating Agents; D004268:DNA-Binding Proteins; D007476:Ionophores; D050778:NFATC Transcription Factors; D004533:Egtazic Acid; D016572:Cyclosporine; D019703:Calcineurin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D002118:Calcium