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Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling.

Cho, HJ; Jin, SM; Youn, HD; Huh, K; Mook-Jung, I
Aging cell, 7(2):137-147, 2008
Journal Title
Aging cell
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.
MeSH terms
Active Transport, Cell Nucleus/drug effectsAging/geneticsAging/metabolismAlzheimer Disease/geneticsAlzheimer Disease/metabolismAmyloid Precursor Protein Secretases/analysisAmyloid Precursor Protein Secretases/genetics*Amyloid Precursor Protein Secretases/metabolism*Amyloid beta-Peptides/biosynthesisAmyloid beta-Peptides/pharmacologyAnimalsAspartic Acid Endopeptidases/analysisAspartic Acid Endopeptidases/genetics*Aspartic Acid Endopeptidases/metabolism*Calcineurin/antagonists & inhibitorsCalcineurin/metabolismCalcium/pharmacologyCalcium Signaling/drug effectsCalcium Signaling/genetics*Cells, CulturedChelating Agents/pharmacologyCyclosporine/pharmacologyDNA-Binding ProteinsDisease Models, AnimalEgtazic Acid/pharmacologyEnzyme Activation/drug effectsHumansIonophoresMiceNFATC Transcription Factors/genetics*NFATC Transcription Factors/metabolism*NeuroblastomaPromoter Regions, GeneticUp-Regulation
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Neurology
AJOU Authors
허, 균
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