Department of Biophysics and Chemical Biology, Seoul National University, Seoul 08826, Korea.
Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea.
ACS Chem Neurosci. 2023 Dec 6;14(23):4139-4152. doi: 10.1021/acschemneuro.3c00508. Epub 2023 Nov 28.
Tau protein aggregation and propagation in neurons and surrounding microglia are well-known risk factors for neurodegenerative diseases. Therefore, emerging therapeutic strategies that target neuroinflammatory activity in microglia have the potential to prevent tauopathy. Here, we explored the microglia-mediated neuroprotective function of SB1617 against tau aggregation. Our study revealed that SB1617-inactivated pathogenic M1-like microglia, reduced the secretion of pro-inflammatory cytokines translational regulation, and induced microglial polarization toward the M2 phenotype and phagocytic function. Furthermore, we observed that extracellular pathogenic tau aggregates were eliminated LC3-associated phagocytosis. The efficacy of SB1617 was confirmed in mice with traumatic brain injury in which SB1617 exerted neuroprotective effects by reducing pathogenic tau levels through microglia-mediated anti-inflammatory activity. Our results indicated that SB1617-mediated microglial surveillance with LC3-associated phagocytosis is a critical molecular mechanism in the regulation of tau proteostasis. This study provides new insights into tauopathies and directions for developing novel therapies for neurodegenerative diseases.
神经元和周围小胶质细胞中的 Tau 蛋白聚集和传播是神经退行性疾病的已知风险因素。因此，针对小胶质细胞神经炎症活性的新兴治疗策略有可能预防 Tau 病。在这里，我们探讨了 SB1617 对 Tau 聚集的小胶质细胞介导的神经保护作用。我们的研究表明，SB1617 失活了致病性 M1 样小胶质细胞，减少了促炎细胞因子的分泌，诱导小胶质细胞向 M2 表型和吞噬功能极化。此外，我们观察到细胞外致病性 Tau 聚集体被 LC3 相关的吞噬作用所清除。在创伤性脑损伤的小鼠中，SB1617 的疗效得到了证实，SB1617 通过小胶质细胞介导的抗炎活性降低致病性 Tau 水平发挥神经保护作用。我们的结果表明，SB1617 介导的 LC3 相关吞噬作用的小胶质细胞监视是调节 Tau 稳态的关键分子机制。这项研究为 Tau 病提供了新的见解，并为神经退行性疾病的新型治疗方法指明了方向。
