Wen Wen, Chen Jie, Xiang Junbao, Zhang Shiqi, Liu Jingru, Wang Jie, Wang Ping, Xu Shijun
State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Institute of Material Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Division of Biosciences, University College London, London WC1E6BT, UK.
Chin J Nat Med. 2025 Aug;23(8):909-919. doi: 10.1016/S1875-5364(25)60927-7.
Triggering receptor expressed on myeloid cells 2 (TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta (Aβ) clearance in Alzheimer's disease (AD). Energy metabolic reprogramming (EMR) in microglia induced by TREM2 presents therapeutic targets for cognitive impairment in AD. Jiawei Xionggui Decoction (JWXG) has demonstrated effectiveness in enhancing energy supply, protecting microglia, and mitigating cognitive impairment in APP/PS1 mice. However, the mechanism by which JWXG enhances Aβ phagocytosis through TREM2-mediated EMR in microglia remains unclear. This study investigates how JWXG facilitates microglial phagocytosis and alleviates cognitive deficits in AD through TREM2-mediated EMR. Microglial phagocytosis was evaluated through immunofluorescence staining in vitro and in vivo. The EMR level of microglia was assessed using high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA) kits. The TREM2/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway was analyzed using Western blotting in BV cells. TREM2 BV cells were utilized for reverse validation experiments. The Aβ burden, neuropathological features, and cognitive ability in APP/PS1 mice were evaluated using ELISA kits, immunohistochemistry (IHC), and the Morris water maze (MWM) test. JWXG enhanced both the phagocytosis of EMR disorder-BV cells (EMRD-BV) and increased EMR levels. Notably, these effects were significantly reversed in TREM2 BV cells. JWXG elevated TREM2 expression, adenosine triphosphate (ATP) levels, and microglial phagocytosis in APP/PS1 mice. Additionally, JWXG reduced Aβ-burden, neuropathological lesions, and cognitive deficits in APP/PS1 mice. In conclusion, JWXG promoted TREM2-induced EMR and enhanced microglial phagocytosis, thereby reducing Aβ deposition, improving neuropathological lesions, and alleviating cognitive deficits.
髓系细胞触发受体2（TREM2）介导的小胶质细胞吞噬作用是一个能量消耗密集型过程，在阿尔茨海默病（AD）的β淀粉样蛋白（Aβ）清除中起关键作用。TREM2诱导的小胶质细胞能量代谢重编程（EMR）为AD认知障碍提供了治疗靶点。加味芎归汤（JWXG）已证明在增强能量供应、保护小胶质细胞和减轻APP/PS1小鼠认知障碍方面有效。然而，JWXG通过TREM2介导的小胶质细胞EMR增强Aβ吞噬作用的机制仍不清楚。本研究探讨JWXG如何通过TREM2介导的EMR促进小胶质细胞吞噬作用并减轻AD中的认知缺陷。通过体外和体内免疫荧光染色评估小胶质细胞吞噬作用。使用高效液相色谱（HPLC）和酶联免疫吸附测定（ELISA）试剂盒评估小胶质细胞的EMR水平。使用蛋白质免疫印迹法在BV细胞中分析TREM2/蛋白激酶B（Akt）/雷帕霉素靶蛋白（mTOR）/缺氧诱导因子-1α（HIF-1α）信号通路。利用TREM2基因敲除的BV细胞进行反向验证实验。使用ELISA试剂盒、免疫组织化学（IHC）和莫里斯水迷宫（MWM）试验评估APP/PS1小鼠的Aβ负荷、神经病理学特征和认知能力。JWXG增强了能量代谢紊乱的BV细胞（EMRD-BV）的吞噬作用，并提高了EMR水平。值得注意的是，在TREM2基因敲除的BV细胞中，这些作用显著逆转。JWXG提高了APP/PS1小鼠的TREM2表达、三磷酸腺苷（ATP）水平和小胶质细胞吞噬作用。此外，JWXG降低了APP/PS1小鼠的Aβ负荷、神经病理学损伤和认知缺陷。总之，JWXG促进了TREM2诱导的EMR并增强了小胶质细胞吞噬作用，从而减少Aβ沉积，改善神经病理学损伤并减轻认知缺陷。
