title: Aβ-induced Ca(2+) influx regulates astrocytic BACE1 expression via calcineurin/NFAT4 signals.
abstract: The β-site APP cleaving enzyme (BACE1) is required for the production of β-amyloid peptides, which give rise to β-amyloid (Aβ) deposits in the brains of Alzheimer's disease (AD) patients. In brains, BACE1 is primarily expressed by neurons, however BACE1 expression has also been observed in reactive astrocytes in close proximity to β-amyloid plaques in the brains of aged Tg2576 AD model mice. To date, the direct effects of Aβ on BACE1 gene expression in astrocytes is unknown. We found that Aβ42 or Aβ25-35 treatment induced BACE1 expression in primary astrocytes as well as human astrocytoma cell line. Aβ neurotoxicity has been associated with the disruption of intracellular calcium homeostasis both in neurons and in glial cells. Here, we demonstrated that NFAT4, a transcription factor tightly regulated by the calcium/calmodulin-dependent phosphatase, calcineurin, was activated in astrocytes applied with calcium ionophore or Aβ. Aβ-activated NFAT4 proteins were associated with astrocytic BACE1 gene expression via direct interaction with the BACE1 promoter region.
authors: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors: Seok Min
authors: SM
authors: Jin
authors: Hyun Jin
authors: HJ
authors: Cho
authors: Yong Woo
authors: YW
authors: Kim
authors: Ji Yeon
authors: JY
authors: Hwang
authors: Inhee
authors: I
authors: Mook-Jung
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D050778:NFATC Transcription Factors; C494008:NFATC3 protein, human; D019703:Calcineurin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D002118:Calcium