Abstract：
Delayed neurocognitive recovery (dNCR) is a common complication in geriatric surgical patients. The impact of anesthesia and surgery on patients with neurodegenerative diseases, such as Parkinson\'s disease (PD) or prion disease, has not yet been reported. In this study, we aimed to determine the association between a pre-existing A53T genetic background, which involves a PD-related point mutation, and the development of postoperative dNCR. We observed that partial hepatectomy induced hippocampus-dependent cognitive deficits in 5-month-old A53T transgenic mice, a model of early-stage PD without cognitive deficits, unlike in age-matched wild-type (WT) mice. We respectively examined molecular changes at 6 h, 1 day, and 2 days after partial hepatectomy and observed that cognitive changes were accompanied by weakened angiotensin-(1-7)/Mas receptor [Ang-(1-7)/MasR] axis, increased alpha-synuclein (α-syn) expression and phosphorylation, decreased methylated protein phosphatase-2A (Me-PP2A), and prompted microglia M1 polarization and neuronal apoptosis in the hippocampus at 1 day after surgery. Nevertheless, no changes in blood-brain barrier (BBB) integrity or plasma α-syn levels in either A53T or WT mice. Furthermore, intranasal administration of selective MasR agonist AVE 0991, reversed the mentioned cognitive deficits in A53T mice, enhanced MasR expression, reduced α-syn accumulation and phosphorylation, and attenuated microglia activation and apoptotic response. Our findings suggest that individuals with the A53T genetic background may be more susceptible to developing postoperative dNCR. This susceptibility could be linked to central α-syn accumulation mediated by the weakened Ang-(1-7)/MasR/methyl-PP2A signaling pathway in the hippocampus following surgery, independent of plasma α-syn level and BBB.
摘要：
神经认知恢复延迟（dNCR）是老年手术患者的常见并发症。麻醉和手术对神经退行性疾病患者的影响，如帕金森病（PD）或朊病毒病，尚未报告。在这项研究中,我们的目的是确定预先存在的A53T遗传背景之间的关联，涉及PD相关的点突变，以及术后dNCR的发展。我们观察到部分肝切除术在5个月大的A53T转基因小鼠中引起海马依赖性认知缺陷，没有认知缺陷的早期PD模型，与年龄匹配的野生型（WT）小鼠不同。我们分别检查了6小时的分子变化，1天,和肝部分切除术后2天，观察到认知变化伴随着减弱的血管紧张素-（1-7）/Mas受体[Ang-（1-7）/MasR]轴，α-突触核蛋白（α-syn）表达和磷酸化增加，降低甲基化蛋白磷酸酶-2A（Me-PP2A），术后1天提示海马小胶质细胞M1极化和神经元凋亡。然而，A53T或WT小鼠的血脑屏障（BBB）完整性或血浆α-syn水平均无变化。此外，选择性MasR激动剂AVE0991的鼻内给药，逆转了A53T小鼠的上述认知缺陷，增强的MasR表达，减少α-syn积累和磷酸化，和减弱小胶质细胞活化和凋亡反应。我们的发现表明，具有A53T遗传背景的个体可能更容易发生术后dNCR。这种易感性可能与手术后海马中Ang-（1-7）/MasR/甲基-PP2A信号通路减弱介导的中枢α-syn积累有关，与血浆α-syn水平和BBB无关。
