State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Curr Alzheimer Res. 2019;16(8):710-722. doi: 10.2174/1567205016666190801153751.
Alzheimer's Disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown.
The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively.
RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice.
These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.
阿尔茨海默病（AD）的特征是存在细胞外淀粉样蛋白-β（Aβ）斑块和由微管相关蛋白 tau 组成的神经元内神经原纤维缠结。越来越多的证据表明 tau 病理学在 AD 进展中起着重要作用。白藜芦醇（RSV）先前已被证明通过抑制 Aβ生成和 Aβ诱导的神经细胞毒性对 AD 发挥神经保护作用，但其对 tau 病理学的影响尚不清楚。
通过 Thioflavin T 荧光和透射电子显微镜成像测量 RSV 对 tau 聚集的影响。通过 MTT 测定法评估 RSV 对 tau 寡聚物诱导的细胞毒性的影响，并通过免疫细胞化学测定 N2a 细胞摄取细胞外 tau 的情况。6 月龄雄性 PS19 小鼠通过口服（灌胃）每天一次给予 RSV 或载体 5 周。通过 Morris 水迷宫测试、物体识别测试和 Y 迷宫测试确定认知性能。通过免疫印迹、免疫染色和 ELISA 分别评估大脑中磷酸化 tau、神经胶质、促炎细胞因子（如 TNF-α 和 IL-1β）和突触蛋白（包括突触小体蛋白和 PSD95）的水平。
RSV 显著抑制 tau 聚集和 tau 寡聚物诱导的细胞毒性，并阻止 N2a 细胞摄取细胞外 tau 寡聚物。当应用于 PS19 小鼠时，RSV 治疗有效挽救了认知缺陷，降低了小鼠大脑中磷酸化 tau、神经炎症和突触丢失的水平。
这些发现表明 RSV 对 AD 和其他 tau 病具有有希望的治疗潜力。
