mTORC1-TFEB介导的α-突触核蛋白寡聚化在丙泊酚麻醉手术后POCD中的作用

The effects of prolonged propofol anesthesia and surgery on the fragile brain of the elderly are a hot topic of clinical concern. Both international and our studies suggest that long-term propofol intravenous anesthesia and noxious stimulation of surgery can inhibit autophagy of neurons in brain, leading to abnormal accumulation and oligomerization of α-synuclein (α-syn), and aggravate POCD. However, the exact molecular mechanism is still unclear. Given that the mTORC1-TFEB autophagy pathway is an important clearance mechanism for α-syn oligomers，we hypothesize that anesthesia/surgery resulting in inhibition of the mTORC1-TFEB autophagy pathway, dysfunction of α-syn oligomers clearance, ultimately leading to synaptic dysfunction may be an important molecular mechanism of POCD. This project intends to explore the relationship between inhibition of mTORC1-TFEB autophagy pathway and α-syn oligomerization in related brain regions (hippocampus, prefrontal lobe, amygdala and striatum) after prolonged propofol anesthesia/surgery in aged rats, and the molecular mechanism between this signaling pathway and α-syn oligomerization in POCD. On this basis, we are also to explore the change rules of neuronal alpha-syn exosomes and its biological significance in perioperative period. The results may provide new experimental basis for the mechanism study and intervention of POCD.

长时间丙泊酚麻醉及手术应激对老年脆弱大脑认知功能的影响是围术期关注的热点问题。国际上及我们的前期研究均提示：长时间丙泊酚静脉麻醉及手术伤害性刺激可抑制脑内神经元自噬，导致α-突触核蛋白异常积聚及寡聚化，引发POCD，但其确切分子机制尚不清楚。鉴于mTORC1-TFEB自噬通路是α-syn寡聚体重要的清除机制，我们推测麻醉/手术导致mTORC1-TFEB自噬通路抑制，α-syn寡聚体清除障碍，最终导致突触功能受损可能是POCD的关键分子机制。本项目拟以老年大鼠为研究对象，通过基因与药物干预mTORC1-TFEB自噬通路，探究长时间丙泊酚麻醉/手术后该通路与相关脑区（海马、前额叶、杏仁核与纹状体）α-syn寡聚化的关系，以及该信号通路与α-syn寡聚化在POCD中的分子机制。在此基础上，探究围术期神经元外泌体α-syn的变化规律及其生物学意义。研究结果将为POCD的机制研究及干预提供实验依据。

长时间丙泊酚麻醉及手术应激对老年脆弱大脑认知功能的影响是围术期关注的热点问题。国际上及我们的研究均提示：长时间丙泊酚静脉麻醉及手术伤害性刺激可抑制脑内神经元自噬，导致α-突触核蛋白异常积聚及寡聚化，引发POCD，但其确切分子机制尚不清楚。鉴于mTORC1-TFEB自噬通路是α-syn寡聚体重要的清除机制，我们推测麻醉/手术导致mTORC1-TFEB自噬通路抑制，α-syn寡聚体清除障碍，最终导致突触功能受损可能是POCD的关键分子机制。本项目以老年大鼠及转基因鼠为研究对象，通过基因与药物干预mTORC1-TFEB自噬通路，探究了长时间丙泊酚麻醉/手术后该通路与相关脑区α-syn寡聚化的关系，以及该信号通路与α-syn寡聚化在POCD中的分子机制。在此基础上，探究围术期神经元外泌体α-syn的变化规律及其生物标志物潜能。研究结果发现：丙泊酚静脉麻醉/手术后，造成老年大鼠相关脑mTORC1/TFEB自噬通路抑制致α-syn清除障碍并寡聚化，进一步损伤突触功能及神经递质释放，这些改变是引起老年脆弱大脑POCD的重要病理机制；通过调控mTORC1/TFEB自噬通路，诱导神经元细胞自噬，调控 α-syn 寡聚化程度，可以有效调控 POCD，其机制可能与自噬抑制α-syn 寡聚化，改善突触功能有关；血浆脑源性外泌体α-syn的变化具有一定的生物标志物潜能。本项目研究结果将深化对POCD的机制认识，并为POCD的防治提供基础及临床转化依据。