Wang Cailin, Chang Yanmin, Zhu Jiahui, Wu Yanqing, Jiang Xingjun, Zheng Siyi, Li Gang, Ma Rong
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Exp Neurol. 2023 May;363:114355. doi: 10.1016/j.expneurol.2023.114355. Epub 2023 Mar 1.
Alzheimer's disease (AD) is a complicated and refractory neurodegenerative disease that is typically characterized by memory loss and multiple cognitive impairments. Multiple neuropathology including hyperphosphorylated tau formation and accumulation, dysregulated mitochondrial dynamics, and synaptic damage have been well implicated in the progression of AD. So far, there are few valid and effective therapeutic modalities for treatment. AdipoRon, a specific adiponectin (APN) receptor agonist, is reported to be associated with cognitive deficits improvement. In the present study, we attempt to explore the potential therapeutic effects of AdipoRon on tauopathy and related molecular mechanisms.
In this study, P301S tau transgenic mice were used. The plasma level of APN was detected by ELISA. The level of APN receptors was qualified by western blot and immunofluorescence. 6-month-old mice were treated with AdipoRon or vehicle by oral administration daily for 4 months. The benefits of AdipoRon on tau hyperphosphorylation, mitochondrial dynamics, and synaptic function were detected by western blot, immunohistochemistry, immunofluorescence, Golgi staining and transmission electron microscopy. Morris water maze test and novel object recognition test were conducted to explore memory impairments.
Compared with wild-type mice, the expression of APN in plasma in 10-month-old P301S mice was obviously decreased. APN receptors in the hippocampus were increased in the hippocampus. AdipoRon treatment significantly rescued memory deficits in P301S mice. Besides, AdipoRon treatment was also detected to improve synaptic function, enhance mitochondrial fusion, and mitigate hyperphosphorylated tau accumulation in P301S mice and SY5Y cells. Mechanistically, AMPK/SIRT3 and AMPK/GSK3β signaling pathways are demonstrated to be involved in AdipoRon-mediated benefits on mitochondrial dynamics and tau accumulation, respectively, and inhibition of AMPK related pathways showed counteracted effects.
Our results demonstrated that AdipoRon treatment could significantly mitigate tau pathology, improve synaptic damage, and restore mitochondrial dynamics via the AMPK-related pathway, which provides a novel potential therapeutic approach to retard the progression of AD and other tauopathies diseases.
阿尔茨海默病（AD）是一种复杂难治的神经退行性疾病，其典型特征为记忆丧失和多种认知障碍。多种神经病理学变化，包括过度磷酸化tau蛋白的形成与积累、线粒体动力学失调以及突触损伤，均与AD的进展密切相关。迄今为止，针对AD的治疗几乎没有有效且可靠的治疗方法。AdipoRon是一种特异性脂联素（APN）受体激动剂，据报道其与认知缺陷的改善有关。在本研究中，我们试图探究AdipoRon对tau蛋白病的潜在治疗作用及其相关分子机制。
本研究使用P301S tau转基因小鼠。采用酶联免疫吸附测定（ELISA）法检测血浆中APN水平。通过蛋白质免疫印迹法和免疫荧光法鉴定APN受体水平。对6月龄小鼠每日经口给予AdipoRon或赋形剂，持续4个月。采用蛋白质免疫印迹法、免疫组织化学法、免疫荧光法、高尔基染色法和透射电子显微镜法检测AdipoRon对tau蛋白过度磷酸化、线粒体动力学和突触功能的作用。进行莫里斯水迷宫试验和新物体识别试验以探究记忆障碍情况。
与野生型小鼠相比，10月龄P301S小鼠血浆中APN的表达明显降低，海马中的APN受体增加。AdipoRon治疗显著改善了P301S小鼠的记忆缺陷。此外，还检测到AdipoRon治疗可改善P301S小鼠和SY5Y细胞的突触功能，增强线粒体融合，并减轻过度磷酸化tau蛋白的积累。从机制上讲，AMPK/SIRT3和AMPK/GSK3β信号通路分别参与了AdipoRon对线粒体动力学和tau蛋白积累的有益作用，抑制AMPK相关通路则显示出相反的效果。
我们的结果表明，AdipoRon治疗可通过AMPK相关途径显著减轻tau蛋白病变，改善突触损伤，并恢复线粒体动力学，这为延缓AD和其他tau蛋白病的进展提供了一种新的潜在治疗方法。
