Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG), 35, Morioka, Obu, Aichi 474-8511, Japan.
Mol Neurodegener. 2011 Jul 5;6:47. doi: 10.1186/1750-1326-6-47.
Recently, several lines of evidence have shown the aberrant expression of cell-cycle-related proteins and tumor suppressor proteins in vulnerable neurons of the Alzheimer's disease (AD) brain and transgenic mouse models of AD; these proteins are associated with various paradigms of neuronal death. It has been reported that ATBF1 induces cell cycle arrest associated with neuronal differentiation in the developing rat brain, and that gene is one of the candidate tumor suppressor genes for prostate and breast cancers in whose cells overexpressed ATBF1 induces cell cycle arrest. However, the involvement of ATBF1 in AD pathogenesis is as yet unknown.
We found that ATBF1 was up-regulated in the brains of 17-month-old Tg2576 mice compared with those of age-matched wild-type mice. Moreover, our in vitro studies showed that Aβ1-42 and DNA-damaging drugs, namely, etoposide and homocysteine, increased the expression ATBF1 level in primary rat cortical neurons, whereas the knockdown of ATBF1 in these neurons protected against neuronal death induced by Aβ1-42, etoposide, and homocysteine, indicating that ATBF1 mediates neuronal death in response to these substances. In addition, we found that ATBF1-mediated neuronal death is dependent on ataxia-telangiectasia mutated (ATM) because the blockage of ATM activity by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 function in neuronal death. Furthermore, Aβ1-42 phosphorylates ATM, and ATBF1 interacts with phosphorylated ATM.
To the best of our knowledge, this is the first report that Aβ1-42 and DNA-damaging drugs increased the ATBF1 expression level in primary rat cortical neurons; this increase, in turn, may activate ATM signaling responsible for neuronal death through the binding of ATBF1 to phosphorylated ATM. ATBF1 may therefore be a suitable target for therapeutic intervention of AD.
最近，有几项证据表明，阿尔茨海默病（AD）大脑和 AD 转基因小鼠模型中易损神经元中细胞周期相关蛋白和肿瘤抑制蛋白的异常表达与各种神经元死亡模式有关。据报道，ATBF1 在发育中的大鼠脑中诱导与神经元分化相关的细胞周期停滞，该基因是前列腺癌和乳腺癌的候选肿瘤抑制基因之一，在这些细胞中过表达 ATBF1 可诱导细胞周期停滞。然而，ATBF1 参与 AD 发病机制尚不清楚。
我们发现与年龄匹配的野生型小鼠相比，17 个月大的Tg2576 小鼠脑中 ATBF1 上调。此外，我们的体外研究表明，Aβ1-42 和 DNA 损伤药物，即依托泊苷和同型半胱氨酸，增加了原代大鼠皮质神经元中 ATBF1 的表达水平，而这些神经元中 ATBF1 的敲低可防止 Aβ1-42、依托泊苷和同型半胱氨酸诱导的神经元死亡，表明 ATBF1 介导了对这些物质的神经元死亡。此外，我们发现 ATBF1 介导的神经元死亡依赖于共济失调毛细血管扩张突变（ATM），因为 ATM 抑制剂、咖啡因和 KU55933 处理阻断 ATM 活性会使 ATBF1 在神经元死亡中的功能丧失。此外，Aβ1-42 磷酸化 ATM，ATBF1 与磷酸化 ATM 相互作用。
据我们所知，这是第一项报道 Aβ1-42 和 DNA 损伤药物增加原代大鼠皮质神经元中 ATBF1 表达水平的报告；这种增加反过来可能通过 ATBF1 与磷酸化 ATM 的结合激活 ATM 信号，导致神经元死亡。因此，ATBF1 可能是 AD 治疗干预的合适靶点。
