AdipoRon mitigates tau pathology and restores mitochondrial dynamics via AMPK-related pathway in a mouse model of Alzheimer's disease

莫里斯水上航行任务 安普克 海马体 神经科学 疾病 陶氏病 海马结构 MFN2型 医学 免疫印迹 神经退行性变 线粒体融合 内科学 生物 磷酸化 细胞生物学 蛋白激酶A 生物化学 线粒体DNA 基因
作者
Cailin Wang,Yanmin Chang,Jiahui Zhu,Yanqing Wu,Xingjun Jiang,Shuang Zheng,Gang Li,Rong Ma
出处
期刊:Experimental Neurology [Elsevier]
卷期号:363: 114355-114355 被引量:6
标识
DOI:10.1016/j.expneurol.2023.114355
摘要

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.
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