Abnormal expression of Ten eleven translocation-2 (Tet2) contributes to the pathogenesis of Alzheimer's disease (AD). However, to date, the role of Tet2 in modulating neuronal morphology upon amyloid-β (Aβ)-induced neurotoxicity has not been shown in a mouse model of AD. Here, we have developed a model of injured mouse hippocampal neurons induced by Aβ₄₂ oligomers in vitro. We also investigated the role of Tet2 in injured neurons using recombinant plasmids-induced Tet2 inhibition or over-expression. We found that the reduced expression of Tet2 exacerbated neuronal damage, whereas the increased expression of Tet2 was sufficient to protect neurons against Aβ₄₂ toxicity. Our results indicate that the brains of aged APPswe/PSEN1 double-transgenic (2 × Tg-AD) mice exhibit an increase in Aβ plaque accumulation and a decrease in Tet2 expression. As a result, we have also explored the underlying mechanisms of Tet2 in cognition and amyloid load in 2 × Tg-AD mice via adeno-associated virus-mediated Tet2 knockdown or over-expression. Recombinant adeno-associated virus was microinjected into bilateral dentate gyrus regions of the hippocampus of the mice. Knocking down Tet2 in young 2 × Tg-AD mice resulted in the same extent of cognitive dysfunction as aged 2 × Tg-AD mice. Importantly, in middle-aged 2 × Tg-AD mice, knocking down Tet2 accelerated the accumulation of Aβ plaques, whereas over-expressing Tet2 alleviated amyloid burden and memory loss. Furthermore, our hippocampal RNA-seq data, from young 2 × Tg-AD mice, were enriched with aberrantly expressed lncRNAs and miRNAs that are modulated by Tet2. Tet2-modulated lncRNAs (Malat1, Meg3, Sox2ot, Gm15477, Snhg1) and miRNAs (miR-764, miR-211, and miR-34a) may play a role in neuron formation. Overall, these results indicate that Tet2 may be a potential therapeutic target for repairing neuronal damage and cognitive impairment in AD.

中文翻译：

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10-11 易位-2 (Tet2) 在调节阿尔茨海默病小鼠模型神经元形态和认知中的作用

十一个十一易位-2 (Tet2) 的异常表达有助于阿尔茨海默病 (AD) 的发病机制。然而，迄今为止，尚未在 AD 小鼠模型中显示 Tet2 在调节淀粉样蛋白 β (Aβ) 诱导的神经毒性的神经元形态中的作用。在这里，我们开发了一种由 Aβ ₄₂寡聚体在体外诱导的损伤小鼠海马神经元模型。我们还使用重组质粒诱导的 Tet2 抑制或过表达研究了 Tet2 在受损神经元中的作用。我们发现 Tet2 表达的减少加剧了神经元损伤，而 Tet2 的表达增加足以保护神经元免受 Aβ ₄₂毒性。我们的结果表明，老年 APPswe/PSEN1 双转基因 (2 × Tg-AD) 小鼠的大脑表现出 Aβ 斑块积累增加和 Tet2 表达降低。因此，我们还通过腺相关病毒介导的 Tet2 敲低或过表达探索了 Tet2 在 2 × Tg-AD 小鼠认知和淀粉样蛋白负荷中的潜在机制。将重组腺相关病毒显微注射到小鼠海马的双侧齿状回区域。在年轻的 2 × Tg-AD 小鼠中敲低 Tet2 导致与老年 2 × Tg-AD 小鼠相同程度的认知功能障碍。重要的是，在中年 2 × Tg-AD 小鼠中，敲低 Tet2 加速了 Aβ 斑块的积累，而过度表达 Tet2 减轻了淀粉样蛋白负担和记忆力减退。此外，我们的海马 RNA-seq 数据，来自年轻的 2 × Tg-AD 小鼠，富含由 Tet2 调节的异常表达的 lncRNA 和 miRNA。Tet2 调节的 lncRNA（Malat1、Meg3、Sox2ot、Gm15477、Snhg1）和 miRNA（miR-764、miR-211 和 miR-34a）可能在神经元形成中起作用。总体而言，这些结果表明 Tet2 可能是修复 AD 神经元损伤和认知障碍的潜在治疗靶点。