Shao Nan, Lu Qingyang, Ouyang Zhaorong, Yang Peizheng, Wei Tao, Wang Jinghui, Cai Biao
College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230012, China.
Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, 230012, China.
Metab Brain Dis. 2024 Dec 3;40(1):51. doi: 10.1007/s11011-024-01429-1.
Alzheimer's disease (AD) is a neurodegenerative disorder that occurs with aging. Ganoderma lucidum (Curtis.) P. Karst. (G. lucidum) is a traditional medicinal fungus believed to nourish the brain and anti-aging. Ganoderic acid A (GAA), a triterpenoid from G. lucidum, has demonstrated natural neuroprotective effects. This study aims to explore the therapeutic effect and molecular mechanism of GAA on AD. Systematic network pharmacology identified 95 targets, 8 biological functions, and multiple pathways. The results highlighted MAPK family members as core genes, with MAPK1 (ERK2) showing the highest binding affinity to GAA in molecular docking. In vitro experiments revealed that GAA dose-dependently increased the viability of Aβ-injured HT22 cells and inhibited MAPK pathway-related protein expression. Similar to FR180204, 100 µM GAA significantly reversed ERK protein expression, oxidative stress markers, and mitochondrial damage in AD cell model. GAA also downregulated cleaved caspase-3 protein levels, apoptosis rates, Aβ and p-Tau expression by inhibiting the ERK signaling pathway. The therapeutic effect of GAA on AD was predicted and validated through network pharmacology and in vitro experiments. The ability of GAA to inhibit apoptosis via the ERK/MAPK signaling pathway positions it as a promising candidate for AD treatment.
阿尔茨海默病（AD）是一种随着年龄增长而出现的神经退行性疾病。灵芝（Curtis.）P. Karst.（G. lucidum）是一种传统药用真菌，被认为具有滋养大脑和抗衰老的作用。灵芝酸A（GAA）是灵芝中的一种三萜类化合物，已显示出天然的神经保护作用。本研究旨在探讨GAA对AD的治疗作用及其分子机制。系统网络药理学确定了95个靶点、8种生物学功能和多条信号通路。结果突出了丝裂原活化蛋白激酶（MAPK）家族成员作为核心基因，其中MAPK1（细胞外信号调节激酶2，ERK2）在分子对接中显示出与GAA的最高结合亲和力。体外实验表明，GAA剂量依赖性地增加了Aβ损伤的HT22细胞的活力，并抑制了MAPK信号通路相关蛋白的表达。与FR180204类似，100 μM GAA显著逆转了AD细胞模型中ERK蛋白表达、氧化应激标志物和线粒体损伤。GAA还通过抑制ERK信号通路下调了裂解的半胱天冬酶-3蛋白水平、细胞凋亡率、Aβ和磷酸化tau蛋白的表达。通过网络药理学和体外实验对GAA对AD的治疗作用进行了预测和验证。GAA通过ERK/MAPK信号通路抑制细胞凋亡的能力使其成为AD治疗的一个有前景的候选药物。
