Department of Medical Biology, Faculty of Medicine, Sutçu Imam University, Kahramanmaraş, Turkey.
Department of Medical Biology, Faculty of Medicine, Aydın Adnan Menderes University, Aydın, Turkey.
IUBMB Life. 2024 Dec;76(12):1199-1208. doi: 10.1002/iub.2902. Epub 2024 Aug 19.
To analyze the expressional changes in the PI3K/Akt/GSK-3β pathway and metalloprotease in the cellular Alzheimer's Disease (AD) model with the effect of antioxidant resveratrol. Neuron-like cells were obtained by a two-step method of neuronal differentiation by using a combination of retinoic acid (RA) and brain-derived factor (BDNF) exposure. Then, the application of the amyloid beta peptide 25-35 (Aβ25-35) to the cell culture mimicked the environmental toxicity observed in AD. Afterward, cell viability and apoptosis assays were performed to determine whether the resveratrol exerts a cytotoxic and apoptotic effect. Finally, the expressional changes in genes in the cellular AD model with the effect of resveratrol were analyzed by Real-Time PCR. The analysis in silico was assessed using the STRING V12.0 database in each group. Apoptosis data findings were decreased by 1.5-fold and 2.5-fold respectively by Differentiated+Resveratrol (RES) and RES when compared to control but no significant difference was observed between RES and AD model groups. Real-time PCR analysis results revealed PI3K (3.38-fold), AKT (3.95-fold), and RELN (1.99-fold) expressions were significantly higher (p < .001), and also GSK-3β, TAU, ADAMTS-4, ADAMTS-5, and TIMP-3 gene expression levels were significantly downregulated (2.53-, 1.79-, 2.85-, 4.09-, and 6.62-fold, respectively) in the Differentiated+Aβ + RES groups compared to the Differentiated+Aβ group (p < .001). Network analysis shows the functional enrichment of 23 Alzheimer-related GO terms in the Wnt signaling, proteolysis, and extracellular matrix organization pathways. Resveratrol has inhibited GSK-3β by activating the PI3K/Akt insulin pathway in a neurotoxic environment. In addition, TAU, RELN, metalloproteases, and their inhibitors associated with Alzheimer's pathology have been regulated supporting the neuroprotective effect of resveratrol.
分析抗氧化剂白藜芦醇对细胞阿尔茨海默病（AD）模型中 PI3K/Akt/GSK-3β 通路和金属蛋白酶的表达变化。通过使用维甲酸（RA）和脑源性神经营养因子（BDNF）暴露的两步神经元分化方法获得神经元样细胞。然后，将淀粉样β肽 25-35（Aβ25-35）应用于细胞培养，模拟 AD 中观察到的环境毒性。之后，通过细胞活力和细胞凋亡测定来确定白藜芦醇是否具有细胞毒性和凋亡作用。最后，通过实时 PCR 分析白藜芦醇对细胞 AD 模型中基因的表达变化。使用 STRING V12.0 数据库对每组进行了计算机分析。与对照组相比，分化+白藜芦醇（RES）和 RES 分别使凋亡数据减少了 1.5 倍和 2.5 倍，但 RES 和 AD 模型组之间没有显著差异。实时 PCR 分析结果表明，PI3K（3.38 倍）、AKT（3.95 倍）和 RELN（1.99 倍）的表达明显升高（p<0.001），同时 GSK-3β、TAU、ADAMTS-4、ADAMTS-5 和 TIMP-3 基因表达水平也明显下调（分别为 2.53 倍、1.79 倍、2.85 倍、4.09 倍和 6.62 倍）在分化+Aβ+RES 组与分化+Aβ 组相比（p<0.001）。网络分析显示，Wnt 信号通路、蛋白水解和细胞外基质组织途径中与阿尔茨海默病相关的 23 个 GO 术语具有功能富集性。在神经毒性环境中，白藜芦醇通过激活 PI3K/Akt 胰岛素通路抑制 GSK-3β。此外，与阿尔茨海默病病理相关的 TAU、RELN、金属蛋白酶及其抑制剂也得到了调节，这支持了白藜芦醇的神经保护作用。
