Eudesmin 对淀粉样蛋白-β 肽毒性细胞模型的神经保护特性,Journal of Alzheimer’s Disease

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Eudesmin 对淀粉样蛋白-β 肽毒性细胞模型的神经保护特性
Journal of Alzheimer’s Disease ( IF 3.4 ) Pub Date : 2022-11-26 , DOI: 10.3233/jad-220935
Carolina Castillo ₁ , Gastón Bravo-Arrepol ₂ , Aline Wendt ₁ , Francisco Saez-Orellana ₁ , Camila Millar ₃ , Carlos F Burgos ₃ , Javiera Gavilán ₁ , Carla Pacheco ₄ , Ramón Ahumada-Rudolph ₅ , Mariola Napiórkowska ₆ , Claudia Pérez _{2,

7} , José Becerra _{2,

7} , Jorge Fuentealba ₁ , Jaime R Cabrera-Pardo ₅

Affiliation

背景：阿尔茨海默病（AD）是一种神经退行性疾病，其特征是进行性认知障碍和记忆丧失。AD 的标志之一是淀粉样蛋白-β 肽 (Aβ) 积累，其中可溶性 Aβ 寡聚物 (AβO) 是毒性最强的物质，会破坏突触功能、膜完整性和神经元结构，最终导致细胞凋亡。目前，还没有药物可以阻止 AD 的进展，目前的科学努力集中在寻找新的线索来控制这种疾病。木酚素是从针叶树中提取的化合物，具有多种药用特性。Eudesmin (Eu) 是一种可从南洋杉木材中提取的木脂素，南洋杉是智利的本土树种。这种代谢物显示出一系列生物学特性，包括控制炎症和抗菌作用的能力。目的：本研究分析Eu对AβOs诱导的突触衰竭的神经保护作用。方法：使用神经元模型、PC12 细胞和计算机模拟，我们评估了 Eu (30 nM) 对 AβOs 诱导的毒性的神经保护作用。结果：在小鼠海马的原代培养物中，Eu 保留了针对 AβOs 毒性的突触结构，在相同浓度下维持了稳定的突触前蛋白 SV2 水平。Eu 还通过维持胞质 Ca2+ 瞬变的频率来避免 AβOs 毒性引起的突触衰竭。最后，我们发现 Eu (30 nM) 与 Aβ 聚集过程相互作用，导致 AβOs 毒性降低，这提出了解释 Eu 神经保护活性的另一种机制。结论：我们相信 Eu 代表了一种降低 Aβ 毒性的新型先导化合物，为木酚素作为神经保护剂开辟了新的研究领域。

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Neuroprotective Properties of Eudesmin on a Cellular Model of Amyloid-β Peptide Toxicity

Background:Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. One of the hallmarks in AD is amyloid-β peptide (Aβ) accumulation, where the soluble oligomers of Aβ (AβOs) are the most toxic species, deteriorating the synaptic function, membrane integrity, and neuronal structures, which ultimately lead to apoptosis. Currently, there are no drugs to arrest AD progression, and current scientific efforts are focused on searching for novel leads to control this disease. Lignans are compounds extracted from conifers and have several medicinal properties. Eudesmin (Eu) is an extractable lignan from the wood of Araucaria araucana, a native tree from Chile. This metabolite has shown a range of biological properties, including the ability to control inflammation and antibacterial effects. Objective:In this study, the neuroprotective abilities of Eu on synaptic failure induced by AβOs were analyzed. Methods:Using neuronal models, PC12 cells, and in silico simulations we evaluated the neuroprotective effect of Eu (30 nM) against the toxicity induced by AβOs. Results:In primary cultures from mouse hippocampus, Eu preserved the synaptic structure against AβOs toxicity, maintaining stable levels of the presynaptic protein SV2 at the same concentration. Eu also averted synapsis failure from the AβOs toxicity by sustaining the frequencies of cytosolic Ca2+ transients. Finally, we found that Eu (30 nM) interacts with the Aβ aggregation process inducing a decrease in AβOs toxicity, suggesting an alternative mechanism to explain the neuroprotective activity of Eu. Conclusion:We believe that Eu represents a novel lead that reduces the Aβ toxicity, opening new research venues for lignans as neuroprotective agents.

更新日期：2022-11-26

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