Xu Jiahuan, Jin Hongyu, Li Xiaomeng, Jiang Zhiping, Meng Fanqi, Wang Wei, Li Wen-Yang
Institute of Respiratory and Critical Care Medicine, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
Nat Sci Sleep. 2025 Aug 25;17:1915-1928. doi: 10.2147/NSS.S513304. eCollection 2025.
The triggering receptor expressed on myeloid cells 2 (TREM2) is a new therapeutic target in Alzheimer's disease. However, its role in obstructive sleep apnea (OSA)-related cognitive impairment is still unclear. This study aimed to investigate the effect and regulatory mechanism of TREM2 on cognitive impairment related to OSA.
Since intermittent hypoxia (IH) is the primary pathophysiologic characteristic of OSA, we conducted IH animal and BV2 cell model to investigate the mechanism. knockdown and overexpression cells were created by Lentivirus transfection. A disintegrin and metalloprotease 17 (ADAM17) is the primary enzyme for TREM2 shedding, we used TAPI-1 to inhibit its activity. Morris water maze, Nissl staining, real-time PCR, immunofluorescence, Western blotting, fluorometric assay kit, and enzyme-linked immunosorbent assay were used to explore the molecular mechanism.
The TREM2 levels were decreased in BV2 cells exposed to IH for 24 hours. IH elevated the levels of IL-1β, TNF-α and CD86 in BV2 cells, as well as the levels of p-Tau in conditioned media-cultured HT-22 cells. Conversely, IH reduced the levels of IL-10 and CD206 in BV2 cells. However, these effects were exacerbated in BV2 cells with knockdown, whereas they were mitigated in those with overexpression. Additionally, the ADAM17 activity and soluble TREM2 (sTREM2) levels were increased in BV2 cells subjected to IH. Treatment with TAPI-1, suppressed ADAM17 activity and restored TREM2 expression both in vitro and in vivo. Inhibition of ADAM17 led to a reduction in the expression of CD86, IL-1β, TNF-α and p-Tau levels, while enhancing the expression of CD206, IL10 and cognitive functions.
TREM2 played a protective role in IH-induced neuroinflammation and neuronal injury by promoting microglia M2 polarization. IH caused excessive activation of ADAM17 and resulted in augmented degradation of TREM2. Restoring TREM2 expression by inhibiting ADAM17 indicates a potentially promising therapeutic strategy for cognitive impairment in OSA.
髓系细胞触发受体2（TREM2）是阿尔茨海默病的一个新治疗靶点。然而，其在阻塞性睡眠呼吸暂停（OSA）相关认知障碍中的作用仍不清楚。本研究旨在探讨TREM2对OSA相关认知障碍的影响及调控机制。
由于间歇性缺氧（IH）是OSA的主要病理生理特征，我们建立了IH动物模型和BV2细胞模型来研究其机制。通过慢病毒转染构建TREM2基因敲低和过表达细胞。去整合素和金属蛋白酶17（ADAM17）是TREM2脱落的主要酶，我们使用TAPI-1抑制其活性。采用Morris水迷宫、尼氏染色、实时PCR、免疫荧光、蛋白质印迹、荧光测定试剂盒和酶联免疫吸附测定等方法来探究分子机制。
暴露于IH 24小时的BV2细胞中TREM2水平降低。IH升高了BV2细胞中IL-1β、TNF-α和CD86的水平，以及条件培养基培养的HT-22细胞中p-Tau的水平。相反，IH降低了BV2细胞中IL-10和CD206的水平。然而，在TREM2基因敲低的BV2细胞中这些效应加剧，而在TREM2过表达的细胞中则减轻。此外，暴露于IH的BV2细胞中ADAM17活性和可溶性TREM2（sTREM2）水平升高。用TAPI-1处理在体外和体内均抑制了ADAM17活性并恢复了TREM2表达。抑制ADAM17导致CD8, IL-1β, TNF-α和p-Tau水平的表达降低，同时增强了CD206、IL-10的表达和认知功能。
TREM2通过促进小胶质细胞M2极化在IH诱导的神经炎症和神经元损伤中发挥保护作用。IH导致ADAM17过度激活并导致TREM2降解增加。通过抑制ADAM17恢复TREM2表达为OSA认知障碍提供了一种潜在的有前景的治疗策略。
