PGC-1α/FNDC5/BDNF途径介导Apelin-13改善慢性应激性学习记忆损伤机制研究

Chronic stress induces memory impairment in cognitive dysfunction. Applicant reported that apelin, an endogenous ligand of G-protein-coupled receptor (APJ), can improve memory impairment with chronic stress in rats. However，the molecular mechanism of apelin-13-induced memory impairment remains unclear. According to that, the scientific hypothesis“PGC-1α/FNDC5/BDNF pathway mediates apelin-13 to improve chronic stress-induced memory impairment” can be proposed. We adopt chronic unpredicted mild stress (CUMS) and other methods to explore whether CUMS can reduce the expressions of hippocampus apelin-13 and APJ in rats. To confirm whether CUMS can decrease the expressions of hippocampus PGC-1、FNDC5 and BDNF in rats. To clarify whether apelin-13 reverses the down-regulation of PGC-1α/FNDC5/ BDNF signaling induced by chronic stress. To investigate PGC-1α/FNDC5/BDNF pathway mediates apelin-13 to improve chronic stress-induced memory impairment. From the new perspective that PGC-1α/FNDC5/BDNF signaling, we evoke a new molecular mechanism that apelin/APJ system promote chronic stress-induced memory impairment. The APJ receptor will be a novel target for Alzheimer’s disease and other cognitive-related diseases.

慢性应激引起记忆损伤等认知功能障碍。申请者团队前期报道 G蛋白偶联受体APJ内源性配体apelin-13改善大鼠慢性应激诱导记忆损伤，机制未明。据此提出“PGC-1α/ FNDC5 /BDNF途径介导apelin-13改善慢性应激诱导记忆损伤”的科学假说。本课题拟采用慢性不可预知应激(CUMS)等方法，观察CUMS 是否引起apelin-13及APJ的下调作用；探讨CUMS 是否引起PGC-1α、FNDC5及BDNF的下调作用；明确apelin-13是否逆转CUMS引起的PGC-1α/ FNDC5/BDNF下调作用；阐明PGC-1α/ FNDC5/ BDNF途径介导apelin-13改善大鼠慢性应激诱导记忆损伤。课题从PGC-1α/ FNDC5/BDNF途径，揭示apelin-13/APJ系统改善慢性应激诱导记忆损伤新机理，APJ受体将成为治疗认知障碍疾病药物新靶标。

慢性应激可诱导神经元凋亡，损害海马神经发生，从而导致抑郁样行为。我们之前的研究发现，一种新的神经肽apelin-13及其受体可以改善大鼠的认知障碍和抑郁样行为，但其潜在机制尚不清楚。本研究旨在探讨apelin-13在认知障碍和抑郁样行为中的分子机制。采用4周慢性不可预测轻度应激(CUMS)建立大鼠抑郁模型。最后1周，每天给药Apelin-13(2ug/d)。对小鼠进行了尾悬试验(TST)和蔗糖偏好试验(SPT)。通过新物体识别测试(NOR)识别指标和Morri’s水迷宫(MWM)中穿越隐藏平台的次数建立认知功能。western blot检测p-AMPK、AMPK、BDNF、FNDC5和PGC-1α蛋白的表达。用碘化钾(popidium碘化物，PI)和流式细胞仪检测细胞凋亡。高尔基染色观察海马CA1区棘突树突状分支。测定海马超氧化物歧化酶(SOD)和谷胱甘肽-过氧化物酶(GSH-PX)活性。结果表明，apelin-13改善认知功能损伤，改善抑郁样行为。此外，apelin-13可通过PGC-1α/FNDC5/BDNF通路显著抑制神经元凋亡。综上所述，apelin-13可通过保护神经元功能发挥抗抑郁作用，这可能与AMPK/PGC-1α/FNDC5/BDNF通路的激活有关。