Alzheimer′s disease (AD) has a multifactorial etiology, which requires a single multi-target approach for an efficient treatment. We have focused on E2F4, a transcription factor that regulates cell quiescence and tissue homeostasis, controls gene networks affected in AD, and is upregulated in the brain of Alzheimer′s patients and of APPswe/PS1dE9 and 5xFAD transgenic mice. E2F4 contains an evolutionarily-conserved Thr-motif that, when phosphorylated, modulates its activity, thus constituting a potential target for intervention. Here we show that neuronal expression in 5xFAD mice of a dominant negative form of E2F4 lacking this Thr-motif (E2F4DN) potentiates a transcriptional program consistent with the attenuation of the immune response and global brain homeostasis. This correlates with reduced microgliosis and astrogliosis, modulation of Aβ proteostasis, and blockade of neuronal tetraploidization. Moreover, E2F4DN prevents cognitive impairment and body weight loss, a known somatic alteration associated with AD. Our finding is relevant for AD, since E2F4 is expressed in cortical neurons from Alzheimer patients in association with Thr-specific phosphorylation, as evidenced by an anti-E2F4/anti-phosphoThr proximity ligation assay. We propose E2F4DN-based gene therapy as a promising multifactorial approach against AD.

中文翻译：

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E2F4作为对抗阿尔茨海默氏病的单一多因素靶标

阿尔茨海默氏病（AD）具有多种病因，这就需要采用单一的多目标方法来进行有效治疗。我们专注于E2F4，这是一种调节细胞静止和组织稳态，控制AD中受影响的基因网络的转录因子，并且在阿尔茨海默氏病患者以及APPswe / PS1dE9和5xFAD转基因小鼠的大脑中被上调。E2F4包含进化上保守的Thr-基序，该基团在被磷酸化时调节其活性，从而构成了潜在的干预靶标。在这里，我们显示了在缺乏这种Thr-motif（E2F4DN）的E2F4显性负型5xFAD小鼠中的神经元表达，可增强转录程序，从而减弱免疫反应和实现整体脑稳态。这与小胶质细胞减少症和星形胶质细胞减少症相关，调节Aβ蛋白稳态和神经元四倍体化的阻滞。此外，E2F4DN可防止认知障碍和体重减轻，这是已知的与AD相关的体细胞改变。我们的发现与AD相关，因为E2F4在Alzheimer患者的皮质神经元中与Thr特异的磷酸化相关联，这是通过抗E2F4 / anti-phosphoThr邻近连接测定法证明的。我们建议基于E2F4DN的基因治疗作为有希望的针对AD的多因素方法。如抗E2F4 / anti-phosphoThr邻近连接试验所证明。我们建议基于E2F4DN的基因治疗作为有希望的针对AD的多因素方法。如抗E2F4 / anti-phosphoThr邻近连接试验所证明。我们建议基于E2F4DN的基因治疗作为有希望的针对AD的多因素方法。