Neuronal c-Abl overexpression leads to neuronal loss and neuroinflammation in the mouse forebrain.
Neuronal c-Abl overexpression leads to neuronal loss and neuroinflammation in the mouse forebrain.
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DOI：
10.3233/jad-2011-102025
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Davies P
中科院分区：
文献类型：
--
作者：
Schlatterer SD;Tremblay MA;Acker CM;Davies P
多项免疫细胞化学研究表明，阿贝尔森酪氨酸激酶 (c-Abl) 与阿尔茨海默病 (AD) 患者大脑中的神经炎斑块和神经原纤维缠结有关。此外，c-Abl 已被证明可以磷酸化酪氨酸 394 上的 tau。c-Abl 的活性还参与细胞周期和细胞凋亡的控制。为了检查成年大脑中 c-Abl 激活的后果，我们构建了两株转基因小鼠，表达 c-Abl 的组成型活性形式（AblPP/tTA 小鼠）或其姐妹蛋白 Arg（ArgPP/tTA 小鼠），并具有由强力霉素（Tet-Off）调节的神经元特异性启动子（CamKIIα）。成年小鼠前脑神经元中活性 c-Abl 的表达会导致严重的神经变性，特别是在海马的 CA1 区域。神经元损失之前并伴随着大量的小胶质细胞增生和星形细胞增多。尽管仔细检查，神经胶质细胞中没有发现 c-Abl 表达，这表明神经元 c-Abl 表达是神经胶质增生的原因。相比之下，ArgPP/tTA 小鼠没有神经元丢失或神经胶质增生的证据，尽管蛋白质表达和激酶活性水平与 AblPP/tTA 小鼠相似。鉴于人类 AD 大脑中 c-Abl 激活的证据以及 AblPP/tTA 小鼠的病理表型，异常的 c-Abl 活性很可能在神经退行性疾病中发挥作用。
Several immunocytochemical studies have revealed that Abelson tyrosine kinase (c-Abl) is associated with both neuritic plaques and neurofibrillary tangles in the brains of patients with Alzheimer’s disease (AD). Additionally, c-Abl has been shown to phosphorylate tau on tyrosine 394. The activity of c-Abl is also involved in the control of the cell cycle and apoptosis. To examine the consequences of c-Abl activation in the adult brain, we have constructed two lines of transgenic mice expressing either a constitutively active form of c-Abl (AblPP/tTA mice) or its sister protein, Arg (ArgPP/tTA mice), with a neuron-specific promoter (CamKIIα) regulated by doxycycline (Tet-Off). Expression of active c-Abl in adult mouse forebrain neurons results in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocyctosis. Despite careful examination, no c-Abl expression is found in glial cells, indicating that neuronal c-Abl expression is responsible for the gliosis. In contrast, ArgPP/tTA mice have no evidence of neuronal loss or gliosis, even though protein expression and kinase activity levels are similar to those in the AblPP/tTA mice. Given the evidence of c-Abl activation in the human AD brain combined with the pathological phenotype of AblPP/tTA mice, it is likely that aberrant c-Abl activity may play a role in neurodegenerative disease.