Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Department of Neuroinflammation and Brain Fatigue Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Mol Neurobiol. 2019 May;56(5):3404-3419. doi: 10.1007/s12035-018-1307-2. Epub 2018 Aug 20.
Microglial activation is a pathological feature of many neurodegenerative diseases and the role of cellular lipids in these diseases is mostly unknown. It was known that the special ether lipid plasmalogens (Pls) were reduced in the brain and blood samples of Alzheimer's disease (AD) patients. It has recently been reported that the oral ingestion of scallop-derived Pls (sPls) improved cognition among mild AD patients, which led us to investigate the role of sPls in the microglial activation. We used the lipopolysaccharides (LPS)-induced microglial activation model and found that sPls inhibit the LPS-mediated TLR4 endocytosis and the downstream caspases activation. By using the specific inhibitors, we also confirmed that the TLR4 endocytosis and the caspases activation strictly controlled the pro-inflammatory cytokine expression. In addition, the reduction of cellular Pls by sh-RNA-mediated knockdown of GNPAT (glyceronephosphate O-acyltransferase), a Pls synthesizing enzyme, enhanced the endocytosis of TLR4 and activation of caspase-3 which resulted in the enhanced pro-inflammatory cytokine expression. We also report for the first time that the TLR4 endocytosis was significantly higher in the cortex of aged mice and AD model mice brains, proposing a significant link between the age-related reduction of Pls and microglial activation. Interestingly, the sPls drinking in AD model mice significantly reduced the TLR4 endocytosis. Our cumulative data indicates that the cellular Pls attenuate the microglial activation by maintaining the endocytosis of TLR4, suggesting a possible mechanism of the cognition improvement effect of sPls among mild AD patients.
小胶质细胞活化是许多神经退行性疾病的病理特征，细胞脂质在这些疾病中的作用大多未知。已知特殊醚脂脑苷脂（Pls）在阿尔茨海默病（AD）患者的大脑和血液样本中减少。最近有报道称，口服扇贝来源的 Pls（sPls）可改善轻度 AD 患者的认知能力，这促使我们研究 sPls 在小胶质细胞活化中的作用。我们使用脂多糖（LPS）诱导的小胶质细胞活化模型，发现 sPls 抑制 LPS 介导的 TLR4 内吞作用和下游胱天蛋白酶激活。通过使用特异性抑制剂，我们还证实 TLR4 内吞作用和胱天蛋白酶激活严格控制促炎细胞因子的表达。此外，通过 GNPAT（甘油磷酸 O-酰基转移酶）shRNA 介导的敲低降低细胞 Pls，一种 Pls 合成酶，增强了 TLR4 的内吞作用和 caspase-3 的激活，导致促炎细胞因子表达增强。我们还首次报道 TLR4 的内吞作用在老年小鼠和 AD 模型小鼠大脑皮质中显著升高，提出了 Pls 与年龄相关减少和小胶质细胞活化之间的重要联系。有趣的是，AD 模型小鼠中 sPls 的饮用显著降低了 TLR4 的内吞作用。我们的累积数据表明，细胞 Pls 通过维持 TLR4 的内吞作用来减弱小胶质细胞的活化，这表明 sPls 在轻度 AD 患者中改善认知的可能机制。
