Fulvic Acid Inhibits Aggregation and Promotes Disassembly of Tau Fibrils Associated with Alzheimer's Disease
Fulvic Acid Inhibits Aggregation and Promotes Disassembly of Tau Fibrils Associated with Alzheimer's Disease
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DOI：
10.3233/jad-2011-110623
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发表时间：
2011-01-01
影响因子：
4
通讯作者：
Maccioni, Ricardo B.
中科院分区：
文献类型：
--
作者：
Cornejo, Alberto;Jimenez, Jose M.;Maccioni, Ricardo B.
阿尔茨海默病是一种神经退行性疾病，涉及细胞外斑块（β 淀粉样蛋白）和细胞内 tau 蛋白缠结。最近，由于可溶性肽或寡聚体转化为不溶性丝，缠结形成已被确定为神经退行性过程中涉及的主要事件。目前，当前的治疗策略针对能够抑制 tau 丝形成或分解它们的天然植物复合物和多酚化合物。然而，只有少数多酚分子能够阻止 tau 聚集，并且针对 tau 的天然药物尚未获得批准。黄腐酸是一种腐殖质，具有多种营养保健特性，具有保护认知障碍的潜在活性。在这项工作中，我们提供的证据表明，tau 蛋白的聚集过程（在体外形成配对螺旋丝 (PHF)）受到黄腐酸的抑制，从而影响原纤维的长度及其形态。此外，我们还研究了黄腐酸是否能够分解预先形成的 PHF。我们表明，黄腐酸是一种针对预形成原纤维的活性化合物，通过减少 PHF 的长度影响整个结构，并且可能在疏水水平上起作用，正如我们通过原子力技术观察到的那样。因此，黄腐酸可能为开发利用天然产品治疗阿尔茨海默病的潜在疗法提供新的见解。
Alzheimer's disease is a neurodegenerative disorder involving extracellular plaques (amyloid-beta) and intracellular tangles of tau protein. Recently, tangle formation has been identified as a major event involved in the neurodegenerative process, due to the conversion of either soluble peptides or oligomers into insoluble filaments. At present, the current therapeutic strategies are aimed at natural phytocomplexes and polyphenolics compounds able to either inhibit the formation of tau filaments or disaggregate them. However, only a few polyphenolic molecules have emerged to prevent tau aggregation, and natural drugs targeting tau have not been approved yet. Fulvic acid, a humic substance, has several nutraceutical properties with potential activity to protect cognitive impairment. In this work we provide evidence to show that the aggregation process of tau protein, forming paired helical filaments (PHFs) in vitro, is inhibited by fulvic acid affecting the length of fibrils and their morphology. In addition, we investigated whether fulvic acid is capable of disassembling preformed PHFs. We show that the fulvic acid is an active compound against preformed fibrils affecting the whole structure by diminishing length of PHFs and probably acting at the hydrophobic level, as we observed by atomic force techniques. Thus, fulvic acid is likely to provide new insights in the development of potential treatments for Alzheimer's disease using natural products.