Lei Ling, Guo Qian, Cheng Yilei, Gui Yuran, Li Wensheng, Zhao Yiheng, Xu Zhendong, Luo Yong, Wu Gang, Wang Jian-Zhi, Liu Rong, Li Hong-Lian, Wang Xiaochuan
Hubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan University, Wuhan 430056, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China; School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
J Adv Res. 2025 Jun 16. doi: 10.1016/j.jare.2025.06.033.
Tau hyperphosphorylation exhibited in Alzheimer's brains is also commonly observed in aging process, however, the molecular mechanism underlying tau hyperphosphorylation in aging is largely unknown. The nuclear receptor subfamily 4 group A (Nr4a1) has been implicated in various pathophysiological processes including neurodegeneration, and was found to be increased in Alzheimer's brains.
Our study aims to investigate whether and how Nr4a1 promotes age-related tau hyperphosphorylation and cognitive decline.
Firstly, we examined Nr4a1 levels in hippocampus of Alzheimer's patients, SAMP8 and aged mice. Tau phosphorylation levels were evaluated in hippocampal Nr4a1-overexpressed wild-type mice. Bulk RNA sequencing was performed to gain insight into the molecular mechanism by which elevated Nr4a1 levels drive tau hyperphosphorylation. shNr4a1 viruses were used to knockdown Nr4a1 in senescent neurons and hippocampus of SAMP8 mice, further, tau phosphorylation levels and cognitive function were evaluated. Molecular docking studies were conducted to explore the interaction between Nr4a1 and AKT.
Our findings revealed that Nr4a1 expression is elevated in the hippocampus of Alzheimer's patients, as well as in the hippocampi of SAMP8 mice and aged mice. Notably, in SAMP8 mice, Nr4a1 expression increased in an age-dependent manner, suggesting a positive correlation between Nr4a1 levels and aging. Further investigation showed that hippocampal overexpression of Nr4a1 in wild-type mice led to tau hyperphosphorylation and cognitive dysfunction, which could be rescued by Nr4a1 knockdown in SAMP8 mice. By means of bulk RNA sequencing, we demonstrated that Nr4a1 induced tau hyperphosphorylation through the inhibition of PI3K/AKT/GSK-3β pathway. Furthermore, blocking Nr4a1-AKT interactions using competitive peptides reversed tau hyperphosphorylation.
These results supported the hypothesis that age-dependent upregulation of Nr4a1 attenuated PI3K/AKT/GSK-3β pathway, leading to tau hyperphosphorylation and cognitive decline. Nr4a1 may represent a promising therapeutic target for mitigating age-related cognitive impairments.
阿尔茨海默病大脑中出现的tau蛋白过度磷酸化在衰老过程中也很常见，然而，衰老过程中tau蛋白过度磷酸化的分子机制在很大程度上尚不清楚。核受体亚家族4 A组（Nr4a1）已被证明参与包括神经退行性变在内的各种病理生理过程，并且在阿尔茨海默病大脑中被发现有所增加。
我们的研究旨在调查Nr4a1是否以及如何促进与年龄相关的tau蛋白过度磷酸化和认知能力下降。
首先，我们检测了阿尔茨海默病患者、SAMP8小鼠和老年小鼠海马中的Nr4a1水平。评估了海马中Nr4a1过表达的野生型小鼠的tau蛋白磷酸化水平。进行了批量RNA测序以深入了解Nr4a1水平升高驱动tau蛋白过度磷酸化的分子机制。使用shNr4a1病毒敲低SAMP8小鼠衰老神经元和海马中的Nr4a1，进一步评估tau蛋白磷酸化水平和认知功能。进行分子对接研究以探索Nr4a1与AKT之间的相互作用。
我们的研究结果表明，Nr4a1在阿尔茨海默病患者的海马以及SAMP8小鼠和老年小鼠的海马中表达升高。值得注意的是，在SAMP8小鼠中，Nr4a1表达呈年龄依赖性增加，表明Nr4a1水平与衰老之间存在正相关。进一步的研究表明，野生型小鼠海马中Nr4a1的过表达导致tau蛋白过度磷酸化和认知功能障碍，而SAMP8小鼠中Nr4a1的敲低可以挽救这种情况。通过批量RNA测序，我们证明Nr4a1通过抑制PI3K/AKT/GSK-3β通路诱导tau蛋白过度磷酸化。此外，使用竞争性肽阻断Nr4a1-AKT相互作用可逆转tau蛋白过度磷酸化。
这些结果支持了以下假设，即Nr4a1的年龄依赖性上调减弱了PI3K/AKT/GSK-3β通路，导致tau蛋白过度磷酸化和认知能力下降。Nr4a1可能是减轻与年龄相关的认知障碍的一个有前景的治疗靶点。
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