Quan Qiankun, Ma Xinxin, Feng JianJun, Li Wanni, Li Xi
Department of Geriatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Psychology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Neuropeptides. 2025 Mar 4;111:102514. doi: 10.1016/j.npep.2025.102514.
Alzheimer's disease (AD) is a neurodegeneration driven by beta-amyloid (Aβ) deposits in the brain involving autophagy dysfunction. Ginsenoside Rg1, a pharmacologically active compound found in ginseng, has possible therapeutic effects for AD. This study discovered that FGR proto-oncogene (FGR) was a therapeutic target of Rg1 in AD and it was possibly involved in autophagy. C57BL/6 J mice were injected with 5 μL (1 μg/mL) Aβ in the right lateral ventricle to establish an AD model. AD mouse hippocampus had high FGR expression. Intragastrically administered Rg1 (40 mg/kg) decreased FGR protein levels in AD mice's hippocampus and improved memory function in AD mice. Both sides of the mice hippocampal fissure were administered with 2 μL lentiviral particles (1 × 10 TU) containing FGR overexpression plasmids. FGR overexpression rendered Rg1 ineffectual in restoring memory function and reducing hippocampal neuron damage. We injected 2 μL lentiviral particles (1 × 10 TU) containing short hairpin RNA plasmids targeting FGR to the mice hippocampal fissures. FGR knockdown improved spatial memory function of AD mice, reduced hippocampal neuron apoptosis, and prevented Aβ accumulation. HT22 cells were transfected with small interfering RNA targeting FGR. FGR knockdown increased the viability of Aβ treated HT22 cells. BACE1 and LC3II/I protein levels were decreased and p62 and SIRT1 were increased in AD mice and cells with FGR knockdown. LC3 was down-regulated after inhibiting FGR expression in Aβ treated hippocampal neurons. In conclusion, Rg1 exerts anti-AD functions by targeting FGR and downregulating its expression.
阿尔茨海默病（AD）是一种由大脑中β-淀粉样蛋白（Aβ）沉积驱动的神经退行性疾病，涉及自噬功能障碍。人参皂苷Rg1是人参中发现的一种具有药理活性的化合物，对AD可能具有治疗作用。本研究发现FGR原癌基因（FGR）是Rg1在AD中的治疗靶点，且可能参与自噬过程。将5 μL（1 μg/mL）Aβ注射到C57BL/6 J小鼠右侧侧脑室以建立AD模型。AD小鼠海马中FGR表达较高。胃内给予Rg1（40 mg/kg）可降低AD小鼠海马中的FGR蛋白水平，并改善AD小鼠的记忆功能。在小鼠海马裂两侧给予2 μL含有FGR过表达质粒的慢病毒颗粒（1×10 TU）。FGR过表达使Rg1在恢复记忆功能和减少海马神经元损伤方面无效。我们将2 μL含有靶向FGR的短发夹RNA质粒的慢病毒颗粒（1×10 TU）注射到小鼠海马裂中。FGR基因敲低改善了AD小鼠的空间记忆功能，减少了海马神经元凋亡，并阻止了Aβ积累。用靶向FGR的小干扰RNA转染HT22细胞。FGR基因敲低增加了Aβ处理的HT22细胞的活力。在AD小鼠和FGR基因敲低的细胞中，β-分泌酶1（BACE1）和微管相关蛋白1轻链3II/I（LC3II/I）蛋白水平降低，而p62和沉默信息调节因子1（SIRT1）增加。在Aβ处理的海马神经元中抑制FGR表达后，LC3被下调。总之，Rg1通过靶向FGR并下调其表达发挥抗AD功能。
