Department of Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, China.
Department of Neurology, Seventh People's Hospital of Jinan City, Jinan, China.
Behav Brain Res. 2021 Sep 24;414:113485. doi: 10.1016/j.bbr.2021.113485. Epub 2021 Jul 21.
MicroRNA-142-5p (miR-142-5p) has been found to be dysregulated in several neurodegenerative disorders. However, little is known about the involvement of miR-142-5p in Alzheimer's disease (AD). Brain angiogenesis inhibitor 3 (BAI3), which belongs to the adhesion-G protein-coupled receptor subgroup, contributes to a variety of neuropsychiatric disorders. Despite its very high expression in neurons, the role of BAI3 in AD remains elusive, and its mechanism at the cellular and molecular levels needs to be further elucidated. The current study sought to investigate whether miR-142-5p influenced BAI3 expression and neuronal synaptotoxicity induced by Aβ, both in APP/PS1 transgenic mice and a cellular model of Alzheimer's disease. Altered expression of miR-142-5p was found in the hippocampus of AD mice. Inhibition of miR-142 could upregulate BAI3 expression, enhance neuronal viability and prevent neurons from undergoing apoptosis. In addition, the reduction of phosphorylation of Synapsin I and calcium/calmodulin-dependent protein kinase II (CaMKII), as well as the expression of PSD-95 in the hippocampus of APP/PS1 transgenic mice, were significantly restored by inhibiting miR-142. Meanwhile, the levels of Aβ, β-APP, BACE-1 and PS-1 in cultured neurons were detected, and the effects of inhibiting miR-142 on spatial learning and memory were also observed. Interestingly, we found that BAI3, an important regulator of excitatory synapses, was a potential target gene of miR-142-5p. Collectively, our findings suggest that miR-142 inhibition can alleviate the impairment of spatial learning and memory, reduce the level of apoptosis, and upregulate the expression of pCaMKII and BAI3 in the hippocampus of APP/PS1 transgenic mice; thus, appropriate interference of miR-142 may provide a potential therapeutic approach to rescue cognitive dysfunction in AD patients.
微小 RNA-142-5p (miR-142-5p) 在几种神经退行性疾病中被发现失调。然而，miR-142-5p 参与阿尔茨海默病 (AD) 的情况知之甚少。脑血管生成抑制剂 3 (BAI3) 属于粘附 G 蛋白偶联受体亚组，有助于多种神经精神疾病。尽管它在神经元中表达非常高，但 BAI3 在 AD 中的作用仍不清楚，其在细胞和分子水平的机制仍需进一步阐明。本研究旨在探讨 miR-142-5p 是否影响 APP/PS1 转基因小鼠和阿尔茨海默病细胞模型中 Aβ 诱导的 BAI3 表达和神经元突触毒性。发现 AD 小鼠海马中 miR-142-5p 的表达发生改变。抑制 miR-142 可上调 BAI3 表达，增强神经元活力并防止神经元凋亡。此外，APP/PS1 转基因小鼠海马中突触素 I 和钙/钙调蛋白依赖性蛋白激酶 II (CaMKII) 磷酸化以及 PSD-95 的表达减少被抑制 miR-142 显著恢复。同时，检测培养神经元中 Aβ、β-APP、BACE-1 和 PS-1 的水平，并观察抑制 miR-142 对空间学习和记忆的影响。有趣的是，我们发现 BAI3 是兴奋性突触的重要调节因子，是 miR-142-5p 的潜在靶基因。总之，我们的研究结果表明，抑制 miR-142 可以减轻 APP/PS1 转基因小鼠海马空间学习和记忆损伤，降低细胞凋亡水平，并上调 pCaMKII 和 BAI3 的表达；因此，适当干预 miR-142 可能为治疗 AD 患者认知功能障碍提供潜在的治疗方法。
