Nowak Katrin, Lange-Dohna Christine, Zeitschel Ulrike, Günther Albrecht, Lüscher Bernhard, Robitzki Andrea, Perez-Polo Regino, Rossner Steffen
Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, Leipzig, Germany.
J Neurochem. 2006 Mar;96(6):1696-707. doi: 10.1111/j.1471-4159.2006.03692.x.
The beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a prerequisite for the generation of beta-amyloid peptides, the principle constituents of senile plaques in the brains of patients with Alzheimer's disease (AD). BACE1 expression and enzymatic activity are increased in the AD brain, but the regulatory mechanisms of BACE1 expression are largely unknown. Here we show that Yin Yang 1 (YY1), a highly conserved and multifunctional transcription factor, binds to its putative recognition sequence within the BACE1 promoter and stimulates BACE1 promoter activity in rat pheochromocytoma 12 (PC12) cells, rat primary neurones and astrocytes. In rat brain YY1 and BACE1 are widely expressed by neurons, but there was only a minor proportion of neurones that co-expressed YY1 and BACE1, suggesting that YY1 is not required for constitutive neuronal BACE1 expression. Resting astrocytes in the untreated rat brain did not display either YY1 or BACE1 immunoreactivity. When chronically activated, however, astrocytes expressed both YY1 and BACE1 proteins, indicating that YY1 is important for the stimulated BACE1 expression by reactive astrocytes. This is further emphasized by the expression of YY1 and BACE1 by reactive astrocytes in proximity to beta-amyloid plaques in the AD brain. Our observations suggest that interfering with expression, translocation or binding of YY1 to its BACE1 promoter-specific sequence may have therapeutic potential for treating patients with AD.
β-位淀粉样前体蛋白裂解酶1（BACE1）是生成β-淀粉样肽的前提条件，β-淀粉样肽是阿尔茨海默病（AD）患者大脑中老年斑的主要成分。在AD大脑中，BACE1的表达和酶活性增加，但BACE1表达的调控机制在很大程度上尚不清楚。在此我们表明，阴阳1（YY1），一种高度保守的多功能转录因子，结合到其在BACE1启动子内的假定识别序列，并在大鼠嗜铬细胞瘤12（PC12）细胞、大鼠原代神经元和星形胶质细胞中刺激BACE1启动子活性。在大鼠大脑中，YY1和BACE1在神经元中广泛表达，但仅一小部分神经元同时表达YY1和BACE1，这表明YY1并非组成型神经元BACE1表达所必需。未经处理的大鼠大脑中的静息星形胶质细胞未显示YY1或BACE1免疫反应性。然而，当长期激活时，星形胶质细胞表达YY1和BACE1蛋白，表明YY1对反应性星形胶质细胞刺激的BACE1表达很重要。AD大脑中靠近β-淀粉样斑的反应性星形胶质细胞中YY1和BACE1的表达进一步强调了这一点。我们的观察结果表明，干扰YY1的表达、易位或其与BACE1启动子特异性序列的结合可能对治疗AD患者具有治疗潜力。
