Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong 518055, China; National R&D Center for Se-rich Agricultural Products Processing, Hubei Engineering Research Center for Deep Processing of Green Se-rich Agricultural Products, School of Modern Industry for Selenium Science and Engineering, Wuhan Polytechnic University, Wuhan 430023, China.
Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong 518055, China.
Phytomedicine. 2023 Jan;109:154555. doi: 10.1016/j.phymed.2022.154555. Epub 2022 Nov 17.
Neurofibrillary tangles comprising hyperphosphorylated tau are vital factors associated with the pathogenesis of Alzheimer's disease (AD). The elimination or reduction of hyperphosphorylated and abnormally aggregated tau is a valuable measure in AD therapy. Esculentoside A (EsA), isolated from Phytolacca esculenta, exhibits pharmacotherapeutic efficacy in mice with amyloid beta-induced AD. However, whether EsA affects tau pathology and its specific mechanism of action in AD mice remains unclear.
To investigate the roles and mechanisms of EsA in cognitive decline and tau pathology in a triple transgenic AD (3 × Tg-AD) mouse model.
EsA (5 and 10 mg/kg) was administered via intraperitoneal injection to 8-month-old AD mice for eight consecutive weeks. Y-maze and novel object recognition tasks were used to evaluate the cognitive abilities of mice. Potential signaling pathways and targets in EsA-treated AD mice were assessed using quantitative proteomic analysis. The NFT levels and hippocampal synapse numbers were investigated using Gallyas-Braak silver staining and transmission electron microscopy, respectively. Western blotting and immunofluorescence assays were used to measure the expression of tau-associated proteins.
EsA administration attenuated memory and recognition deficits and synaptic damage in AD mice. Isobaric tags for relative and absolute quantitation proteomic analysis of the mouse hippocampus revealed that EsA modulated the expression of some critical proteins, including brain-specific angiogenesis inhibitor 3, galectin-1, and Ras-related protein 24, whose biological roles are relevant to synaptic function and autophagy. Further research revealed that EsA upregulated AKT/GSK3β activity, in turn, inhibited tau hyperphosphorylation and promoted autophagy to clear abnormally phosphorylated tau. In hippocampus-derived primary neurons, inhibiting AMP-activated protein kinase (AMPK) activity through dorsomorphin could eliminate the effect of EsA, as revealed by increased tau hyperphosphorylation, downregulated activity AKT/GSK3β, and blocked autophagy.
To our knowledge, this study is the first to demonstrate that EsA attenuates cognitive decline by targeting the pathways of both tau hyperphosphorylation and autophagic clearance in an AMPK-dependent manner and it shows a high reference value in AD pharmacotherapy research.
神经原纤维缠结由过度磷酸化的 tau 组成，是与阿尔茨海默病（AD）发病机制相关的重要因素。消除或减少过度磷酸化和异常聚集的 tau 是 AD 治疗的一个有价值的措施。从商陆中分离得到的 Esculentoside A（EsA）在淀粉样β诱导的 AD 小鼠中具有治疗效果。然而，EsA 是否影响 AD 小鼠的 tau 病理学及其在 AD 小鼠中的具体作用机制尚不清楚。
研究 EsA 在三转基因 AD（3×Tg-AD）小鼠模型中认知下降和 tau 病理学中的作用和机制。
用腹腔注射 EsA（5 和 10mg/kg）连续 8 周治疗 8 个月大的 AD 小鼠。Y 迷宫和新物体识别任务用于评估小鼠的认知能力。使用定量蛋白质组学分析评估 EsA 处理的 AD 小鼠中的潜在信号通路和靶标。使用 Gallyas-Braak 银染色和透射电子显微镜分别检测 NFT 水平和海马突触数。Western blot 和免疫荧光测定用于测量 tau 相关蛋白的表达。
EsA 给药可减轻 AD 小鼠的记忆和识别缺陷以及突触损伤。对小鼠海马体的等重标记相对和绝对定量蛋白质组学分析表明，EsA 调节了一些关键蛋白的表达，包括脑特异性血管生成抑制剂 3、半乳糖凝集素-1 和 Ras 相关蛋白 24，其生物学作用与突触功能和自噬有关。进一步的研究表明，EsA 上调 AKT/GSK3β 活性，进而抑制 tau 过度磷酸化并促进自噬以清除异常磷酸化的 tau。在海马源性原代神经元中，通过 dorsomorphin 抑制 AMP 激活的蛋白激酶（AMPK）活性可以消除 EsA 的作用，表现为 tau 过度磷酸化增加、AKT/GSK3β 活性降低和自噬阻断。
据我们所知，这项研究首次表明，EsA 通过靶向 tau 过度磷酸化和自噬清除的途径，以 AMPK 依赖性方式减轻认知下降，并在 AD 药物治疗研究中具有很高的参考价值。
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