Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
Department of Neurology, The Central Hospital of Wuhan, 26 Shengli Street, Wuhan 430014, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 2):113446. doi: 10.1016/j.intimp.2024.113446. Epub 2024 Oct 29.
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons, abnormal accumulation of α-synuclein (α-syn), and microglial activation. Triggering receptor expressed on myeloid cells 2 (TREM2) regulates multiple functions of microglia in the brain, and several studies have shown that TREM2 variant R47H is a risk factor for PD. However, the regulation of microglia by TREM2 in PD remains poorly understood.
We constructed PD cell and animal models using α-syn preformed fibrils. siRNA knockdown and lentiviral overexpression were used to perturb TREM2 levels in cells, and TREM2 knockout mice and lentiviral overexpression was used in animal models to investigate the effects of TREM2 on microglial function, α-syn-related pathology, and dopaminergic neuron degeneration.
Microglia phagocytosed α-syn preformed fibrils in a concentration- and time-dependent manner, with some capacity to degrade α-syn aggregates. TREM2 expression increased in PD. In the context of PD, TREM2 knockout mice exhibited worsened pathological α-syn spread, decreased microglial reactivity, and increased loss of TH-positive neurons in the substantia nigra compared to wild-type mice. TREM2 overexpression enhanced reactive microglial aggregation towards the pathological site. Cellular experiments revealed that reduced TREM2 impaired microglial phagocytosis and proliferation, but enhanced autophagy via the PI3K/AKT/mTOR pathway.
TREM2 signaling in PD maintains microglial phagocytosis, proliferation, and reactivity, stabilizing autophagy and proliferation via the PI3K/AKT/mTOR pathway. Regulating TREM2 levels may be beneficial in PD treatment.
帕金森病（PD）的特征是多巴胺能神经元丧失、α-突触核蛋白（α-syn）异常积累和小胶质细胞激活。髓样细胞触发受体 2（TREM2）调节大脑中小胶质细胞的多种功能，几项研究表明 TREM2 变体 R47H 是 PD 的风险因素。然而，TREM2 在 PD 中小胶质细胞的调节作用仍知之甚少。
我们使用α-syn 预形成纤维构建了 PD 细胞和动物模型。使用 siRNA 敲低和慢病毒过表达来干扰细胞中的 TREM2 水平，使用 TREM2 敲除小鼠和慢病毒过表达在动物模型中研究 TREM2 对小胶质细胞功能、α-syn 相关病理学和多巴胺能神经元变性的影响。
小胶质细胞以浓度和时间依赖的方式吞噬α-syn 预形成纤维，具有一定的降解α-syn 聚集物的能力。TREM2 在 PD 中表达增加。在 PD 背景下，与野生型小鼠相比，TREM2 敲除小鼠表现出更严重的病理性α-syn 传播、小胶质细胞反应性降低和黑质中 TH 阳性神经元丢失增加。TREM2 过表达增强了向病理性部位的反应性小胶质细胞聚集。细胞实验表明，减少 TREM2 会损害小胶质细胞的吞噬作用和增殖，但通过 PI3K/AKT/mTOR 途径增强自噬。
PD 中的 TREM2 信号通过 PI3K/AKT/mTOR 途径维持小胶质细胞的吞噬作用、增殖和反应性，稳定自噬和增殖。调节 TREM2 水平可能有益于 PD 的治疗。
