Neprilysin gene expression requires binding of the amyloid precursor protein intracellular domain to its promoter: implications for Alzheimer disease
Neprilysin gene expression requires binding of the amyloid precursor protein intracellular domain to its promoter: implications for Alzheimer disease
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DOI：
10.1038/embor.2008.222
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发表时间：
2009-01-01
期刊：
影响因子：
7.7
通讯作者：
Turner, Anthony J.
中科院分区：
文献类型：
--
作者：
Belyaev, Nikolai D.;Nalivaeva, Natalia N.;Turner, Anthony J.
β-淀粉样肽（Aβ）积累会导致神经退行性疾病和阿尔茨海默病；然而，淀粉样蛋白代谢是一个动态过程，存在去除 Aβ 的酶机制。关于淀粉样前体蛋白 (AICD) 的胞内结构域是否调节 Aβ 降解金属蛋白酶脑啡肽酶 (NEP) 的表达存在相当大的争议。通过比较 NEP 表达显着差异的两种神经母细胞瘤细胞系，我们通过染色质免疫沉淀 (ChIP) 表明，AICD 在高 NEP 表达细胞 (NB7) 细胞中直接与 NEP 启动子结合，但在低表达细胞 (SH-SY5Y) 细胞中则不然。 NEP 启动子的甲基化状态不调节这些细胞中的表达，而组蛋白脱乙酰酶抑制剂曲古抑菌素 A 和丙戊酸部分恢复 SH-SY5Y 细胞中的 NEP 表达和活性。 ChIP 分析还揭示了 AICD 与大鼠原代神经元中的 NEP 启动子结合，但在 HUVEC 细胞中则不然。丙戊酸对关键的阿尔茨海默病相关基因的染色质重塑可能提供一种新的治疗策略。
Amyloid beta-peptide (A beta) accumulation leads to neurodegeneration and Alzheimer disease; however, amyloid metabolism is a dynamic process and enzymic mechanisms exist for A beta removal. Considerable controversy surrounds whether the intracellular domain of the amyloid precursor protein (AICD) regulates expression of the A beta-degrading metalloprotease, neprilysin (NEP). By comparing two neuroblastoma cell lines differing substantially in NEP expression, we show by chromatin immunoprecipitation (ChIP) that AICD is bound directly to the NEP promoter in high NEP-expresser (NB7) cells but not in low-expresser (SH-SY5Y) cells. The methylation status of the NEP promoter does not regulate expression in these cells, whereas the histone deacetylase inhibitors trichostatin A and valproate partly restore NEP expression and activity in SH-SY5Y cells. ChIP analysis also reveals AICD binding to the NEP promoter in rat primary neurons but not in HUVEC cells. Chromatin remodelling of crucial Alzheimer disease-related genes by valproate could provide a new therapeutic strategy.