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首页> 外文期刊>Neurobiology of disease >Increased EID1 nuclear translocation impairs synaptic plasticity and memory function associated with pathogenesis of Alzheimer's disease
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Increased EID1 nuclear translocation impairs synaptic plasticity and memory function associated with pathogenesis of Alzheimer's disease

机译：EID1核易位增加削弱了与阿尔茨海默氏病发病机理相关的突触可塑性和记忆功能

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摘要

Though loss of function in CBP/p300, a family of CREB-binding proteins, has been causally associated with a variety of human neurological disorders, such as Rubinstein-Taybi syndrome, Huntington's disease and drug addiction, the role of EP300 interacting inhibitor of differentiation 1 (EID1), a CBP/p300 inhibitory protein, in modulating neurological functions remains completely unknown. Through the examination of EID1 expression and cellular distribution, we discovered that there is a significant increase of EID1 nuclear translocation in the cortical neurons of Alzheimer's disease (AD) patient brains compared to that of control brains. To study the potential effects of EID1 on neurological functions associated with learning and memory, we generated a transgenic mouse model with a neuron-specific expression of human EID1 gene in the brain. Overexpression of EID1 led to an increase in its nuclear localization in neurons mimicking that seen in human AD brains. The transgenic mice had a disrupted neurofilament organization and increase of astrogliosis in the cortex and hippocampus. Furthermore, we demonstrated that overexpression of EID1 reduced hippocampal long-term potentiation and impaired spatial learning and memory function in the transgenic mice. Our results indicated that the negative effects of extra nuclear EID1 in transgenic mouse brains are likely due to its inhibitory function on CBP/p300 mediated histone and p53 acetylation, thus affecting the expression of downstream genes involved in the maintenance of neuronal structure and function. Together, our data raise the possibility that alteration of EID1 expression, particularly the increase of EID1 nuclear localization that inhibits CBP/p300 activity in neuronal cells, may play an important role in AD pathogenesis.
机译：尽管CBP / p300（CREB结合蛋白的一个家族）功能丧失与多种人类神经系统疾病有因果关系，例如鲁宾斯坦-泰比综合征，亨廷顿氏病和药物成瘾，EP300相互作用的分化抑制剂的作用1（EID1），一种CBP / p300抑制蛋白，在调节神经功能方面仍然完全未知。通过检查EID1表达和细胞分布，我们发现与对照组相比，阿尔茨海默氏病（AD）患者大脑皮层神经元中EID1核易位明显增加。为了研究EID1对与学习和记忆有关的神经功能的潜在影响，我们生成了具有人类EID1基因在神经元中特定表达的转基因小鼠模型。 EID1的过表达导致其在神经元中的核定位增加，从而模仿了人类AD脑中的神经元。转基因小鼠的神经丝组织被破坏，皮质和海马的星形胶质细胞增多。此外，我们证明了EID1的过表达减少了转基因小鼠海马的长期增强作用，并损害了空间学习和记忆功能。我们的结果表明，转基因小鼠大脑中多余核EID1的负面影响可能是由于其对CBP / p300介导的组蛋白和p53乙酰化的抑制作用，从而影响了参与维持神经元结构和功能的下游基因的表达。总之，我们的数据提出了EID1表达改变，特别是抑制神经元细胞中CBP / p300活性的EID1核定位增加可能在AD发病机理中发挥重要作用的可能性。

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