Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
Biochem Biophys Res Commun. 2012 Aug 31;425(3):649-55. doi: 10.1016/j.bbrc.2012.07.123. Epub 2012 Jul 27.
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.
β-位点 APP 裂解酶（BACE1）是β-淀粉样肽产生所必需的，β-淀粉样肽会导致阿尔茨海默病（AD）患者大脑中的β-淀粉样蛋白（Aβ）沉积。在大脑中，BACE1 主要由神经元表达，但在老年 Tg2576 AD 模型小鼠大脑中靠近β-淀粉样斑块的反应性星形胶质细胞中也观察到 BACE1 表达。迄今为止，Aβ 对星形胶质细胞中 BACE1 基因表达的直接影响尚不清楚。我们发现 Aβ42 或 Aβ25-35 处理诱导原代星形胶质细胞和人星形细胞瘤细胞系中 BACE1 的表达。Aβ 神经毒性与神经元和神经胶质细胞中细胞内钙稳态的破坏有关。在这里，我们证明了 NFAT4，一种受钙/钙调素依赖性磷酸酶，钙调神经磷酸酶紧密调节的转录因子，在应用钙离子载体或 Aβ 的星形胶质细胞中被激活。通过与 BACE1 启动子区域的直接相互作用，Aβ 激活的 NFAT4 蛋白与星形胶质细胞 BACE1 基因表达相关。
