Department of Histology and Embryology, Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
J Neuroinflammation. 2022 Feb 5;19(1):34. doi: 10.1186/s12974-022-02401-5.
The role of physical exercise in the prevention of Alzheimer's disease (AD) has been widely studied. Microglia play an important role in AD. Triggering receptor expressed in myeloid cells 2 (TREM2) is expressed on microglia and is known to mediate microglial metabolic activity and brain glucose metabolism. However, the relationship between brain glucose metabolism and microglial metabolic activity during running exercise in APP/PS1 mice remains unclear.
Ten-month-old male APP/PS1 mice and wild-type mice were randomly divided into sedentary groups or running groups (AD_Sed, WT_Sed, AD_Run and WT_Run, n = 20/group). Running mice had free access to a running wheel for 3 months. Behavioral tests, [18]F-FDG-PET and hippocampal RNA-Seq were performed. The expression levels of microglial glucose transporter (GLUT5), TREM2, soluble TREM2 (sTREM2), TYRO protein tyrosine kinase binding protein (TYROBP), secreted phosphoprotein 1 (SPP1), and phosphorylated spleen tyrosine kinase (p-SYK) were estimated by western blot or ELISA. Immunohistochemistry, stereological methods and immunofluorescence were used to investigate the morphology, proliferation and activity of microglia.
Long-term voluntary running significantly improved cognitive function in APP/PS1 mice. Although there were few differentially expressed genes (DEGs), gene set enrichment analysis (GSEA) showed enriched glycometabolic pathways in APP/PS1 running mice. Running exercise increased FDG uptake in the hippocampus of APP/PS1 mice, as well as the protein expression of GLUT5, TREM2, SPP1 and p-SYK. The level of sTREM2 decreased in the plasma of APP/PS1 running mice. The number of microglia, the length and endpoints of microglial processes, and the ratio of GLUT5/IBA1 microglia were increased in the dentate gyrus (DG) of APP/PS1 running mice. Running exercise did not alter the number of 5-bromo-2'-deoxyuridine (BrdU)/IBA1 microglia but reduced the immunoactivity of CD68 in the hippocampus of APP/PS1 mice.
Running exercise inhibited TREM2 shedding and maintained TREM2 protein levels, which were accompanied by the promotion of brain glucose metabolism, microglial glucose metabolism and morphological plasticity in the hippocampus of AD mice. Microglia might be a structural target responsible for the benefits of running exercise in AD. Promoting microglial glucose metabolism and morphological plasticity modulated by TREM2 might be a novel strategy for AD treatment.
体力活动在预防阿尔茨海默病（AD）中的作用已得到广泛研究。小胶质细胞在 AD 中发挥重要作用。触发受体表达在髓样细胞 2（TREM2）在小胶质细胞上表达，已知介导小胶质细胞代谢活性和脑葡萄糖代谢。然而，APP/PS1 小鼠跑步运动期间脑葡萄糖代谢与小胶质细胞代谢活性之间的关系尚不清楚。
将 10 月龄雄性 APP/PS1 小鼠和野生型小鼠随机分为安静组或跑步组（AD_Sed、WT_Sed、AD_Run 和 WT_Run，每组 n = 20）。跑步小鼠可自由使用跑步轮 3 个月。进行行为测试、[18]F-FDG-PET 和海马 RNA-Seq。通过 Western blot 或 ELISA 测定小胶质细胞葡萄糖转运蛋白（GLUT5）、TREM2、可溶性 TREM2（sTREM2）、TYRO 蛋白酪氨酸激酶结合蛋白（TYROBP）、分泌型磷蛋白 1（SPP1）和磷酸化脾酪氨酸激酶（p-SYK）的表达水平。免疫组织化学、体视学方法和免疫荧光用于研究小胶质细胞的形态、增殖和活性。
长期自愿跑步可显著改善 APP/PS1 小鼠的认知功能。尽管差异表达基因（DEGs）较少，但基因集富集分析（GSEA）显示 APP/PS1 跑步小鼠中糖代谢途径富集。跑步运动增加了 APP/PS1 小鼠海马的 FDG 摄取，以及 GLUT5、TREM2、SPP1 和 p-SYK 的蛋白表达。APP/PS1 跑步小鼠血浆中 sTREM2 水平降低。APP/PS1 跑步小鼠齿状回（DG）中的小胶质细胞数量、小胶质细胞过程的长度和终点以及 GLUT5/IBA1 小胶质细胞的比例增加。跑步运动并未改变 BrdU/IBA1 小胶质细胞的数量，但降低了 APP/PS1 小鼠海马中的 CD68 免疫活性。
跑步运动抑制了 TREM2 的脱落并维持了 TREM2 蛋白水平，同时促进了 AD 小鼠大脑葡萄糖代谢、小胶质细胞葡萄糖代谢和海马形态可塑性。小胶质细胞可能是跑步运动对 AD 有益的结构靶点。通过 TREM2 调节小胶质细胞葡萄糖代谢和形态可塑性可能是 AD 治疗的一种新策略。
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