Exercise-Induced Reduction of IGF1R Sumoylation Attenuates Neuroinflammation in APP/PS1 Transgenic Mice

神经炎症 相扑蛋白 海马体 海马结构 胰岛素样生长因子1受体 神经科学 炎症 转基因小鼠 化学 细胞生物学 心理学 转基因 生物 受体 内科学 医学 泛素 生物化学 生长因子 基因
作者
Yisheng Chen,Xiaofeng Chen,Zhiwen Luo,Xueran Kang,Yunshen Ge,Renwen Wan,Qian Wang,Zhihua Han,Fangqi Li,Zhongcheng Fan,Yuchun Xie,Beijie Qi,Xintao Zhang,Zhenwei Yang,John H. Zhang,Danping Liu,Yuzhen Xu,Dongyan Wu,Shiyi Chen
出处
期刊:Journal of Advanced Research [Elsevier]
被引量:10
标识
DOI:10.1016/j.jare.2024.03.025
摘要

Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R) and its post-translational modifications, especially sumoylation, is crucial in understanding the progression of AD and exploring novel therapeutic avenues. This study investigates the impact of exercise on the sumoylation of IGF1R and its role in ameliorating AD symptoms in APP/PS1 mice, with a specific focus on neuroinflammation and innovative therapeutic strategies. APP/PS1 mice were subjected to a regimen of moderate-intensity exercise. The investigation encompassed assessments of cognitive functions, alterations in hippocampal protein expressions, neuroinflammatory markers, and the effects of exercise on IGF1R and SUMO1 nuclear translocation. Additionally, the study evaluated the efficacy of KPT-330, a nuclear export inhibitor, as an alternative to exercise. Exercise notably enhanced cognitive functions in AD mice, possibly through modulations in hippocampal proteins, including Bcl-2 and BACE1. A decrease in neuroinflammatory markers such as IL-1β, IL-6, and TNF-α was observed, indicative of reduced neuroinflammation. Exercise modulated the nuclear translocation of SUMO1 and IGF1R in the hippocampus, thereby facilitating neuronal regeneration. Mutant IGF1R (MT IGF1R), lacking SUMO1 modification sites, showed reduced SUMOylation, leading to diminished expression of pro-inflammatory cytokines and apoptosis. KPT-330 impeded the formation of the IGF1R/RanBP2/SUMO1 complex, thereby limiting IGF1R nuclear translocation, inflammation, and neuronal apoptosis, while enhancing cognitive functions and neuron proliferation. Moderate-intensity exercise effectively mitigates Alzheimer's disease (AD) symptoms in mice, primarily by diminishing neuroinflammation, through the reduction of IGF1R Sumoylation. KPT-330, as a potential alternative to physical exercise, enhances the neuroprotective role of IGF1R by inhibiting SUMOylation through targeting XPO1, presenting a promising therapeutic strategy for AD.
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