Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, 08826, Republic of Korea.
Department of Agricultural Biotechnology, Animal Biotechnology Major, and Research Institute of Agriculture and Life Science, Seoul National University, Seoul, 08826, Republic of Korea.
Cell Death Dis. 2018 Nov 14;9(11):1137. doi: 10.1038/s41419-018-1172-y.
Glucocorticoid, a major risk factor of Alzheimer's disease (AD), is widely known to promote microtubule dysfunction recognized as the early pathological feature that culminates in memory deficits. However, the exact glucocorticoid receptor (GR)-mediated mechanism of how glucocorticoid triggers microtubule destabilization and following intracellular transport deficits remains elusive. Therefore, we investigated the effect of glucocorticoid on microtubule instability and cognitive impairment using male ICR mice and human neuroblastoma SH-SY5Y cells. The mice group that was exposed to corticosteroid, the major glucocorticoid form of rodents, showed reduced trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) 1/2 and mitochondria, which are necessary for memory establishment, into the synapse due to microtubule destabilization. In SH-SY5Y cells, cortisol, the major glucocorticoid form of humans, also decreased microtubule stability represented by reduced acetylated α-tubulin to tyrosinated α-tubulin ratio (A/T ratio), depending on the mitochondria GR-mediated pathway. Cortisol translocated the Hsp70-bound GR into mitochondria which thereafter promoted GR-Bcl-2 interaction. Increased ER-mitochondria connectivity via GR-Bcl-2 coupling led to mitochondrial Ca influx, which triggered mTOR activation. Subsequent autophagy inhibition by mTOR phosphorylation increased SCG10 protein levels via reducing ubiquitination of SCG10, eventually inducing microtubule destabilization. Thus, failure of trafficking AMPAR1/2 and mitochondria into the cell terminus occurred by kinesin-1 detachment from microtubules, which is responsible for transporting organelles towards periphery. However, the mice exposed to pretreatment of microtubule stabilizer paclitaxel showed the restored translocation of AMPAR1/2 or mitochondria into synapses and improved memory function compared to corticosterone-treated mice. In conclusion, glucocorticoid enhances ER-mitochondria coupling which evokes elevated SCG10 and microtubule destabilization dependent on mitochondrial GR. This eventually leads to memory impairment through failure of AMPAR1/2 or mitochondria transport into cell periphery.
糖皮质激素是阿尔茨海默病（AD）的主要危险因素，它被广泛认为会促进微管功能障碍，这被认为是导致记忆缺陷的早期病理特征。然而，糖皮质激素触发微管不稳定以及随后的细胞内运输缺陷的确切糖皮质激素受体（GR）介导机制仍不清楚。因此，我们使用雄性 ICR 小鼠和人神经母细胞瘤 SH-SY5Y 细胞研究了糖皮质激素对微管不稳定和认知障碍的影响。暴露于皮质甾酮的小鼠组（啮齿动物的主要糖皮质激素形式）表现出由于微管不稳定导致的 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）1/2 和线粒体向突触内的运输减少，而这些物质对于记忆的建立是必要的。在 SH-SY5Y 细胞中，皮质醇（人类的主要糖皮质激素形式）也通过线粒体 GR 介导的途径降低了微管稳定性，表现为乙酰化α-微管蛋白与酪氨酸化α-微管蛋白的比率（A/T 比率）降低。皮质醇将 Hsp70 结合的 GR 易位到线粒体，此后促进了 GR-Bcl-2 相互作用。通过 GR-Bcl-2 偶联增加 ER-线粒体连接导致线粒体 Ca2+内流，从而触发 mTOR 激活。随后通过 mTOR 磷酸化抑制自噬增加了 SCG10 蛋白水平，通过减少 SCG10 的泛素化，最终诱导微管不稳定。因此，通过动力蛋白-1 从微管上脱离，导致向细胞末端运输细胞器的微管不稳定，从而发生 AMPAR1/2 和线粒体向细胞末端的运输失败。然而，与皮质酮处理的小鼠相比，暴露于微管稳定剂紫杉醇预处理的小鼠显示 AMPAR1/2 或线粒体向突触的再转运得到恢复，并且记忆功能得到改善。总之，糖皮质激素增强了 ER-线粒体偶联，这引发了依赖于线粒体 GR 的 SCG10 和微管不稳定的升高。这最终导致通过 AMPAR1/2 或线粒体向细胞外周的运输失败而导致记忆损伤。
