Pine Bark Polyphenolic Extract Attenuates Amyloid-β and Tau Misfolding in a Model System of Alzheimer's Disease Neuropathology.
Pine Bark Polyphenolic Extract Attenuates Amyloid-β and Tau Misfolding in a Model System of Alzheimer's Disease Neuropathology.
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DOI：
10.3233/jad-190543
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Pasinetti GM
中科院分区：
文献类型：
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作者：
Ono K;Zhao D;Wu Q;Simon J;Wang J;Radu A;Pasinetti GM
植物源多酚类化合物具有多种生物活性，包括较强的抗氧化、抗炎、抗微生物和抗肿瘤活性。人们对开发多酚化合物用于预防和治疗慢性和退行性疾病（例如心血管疾病、癌症和神经疾病，包括阿尔茨海默病（AD））的兴趣越来越大。AD的两种神经病理改变是出现含有tau蛋白的神经元缠结和含有淀粉样β蛋白（Aβ）的细胞外淀粉样沉积。我们的实验室和其他人已经发现，富含原花青素的多酚制剂，如葡萄籽提取物，能够减轻AD动物模型的认知退化和减少脑神经病理学。低花青素是一种松树皮提取物，由低分子量原花青素低聚物（LMW-PAO）组成，包括黄烷-3-醇单元，如儿茶素（C）和表儿茶素（EC）。基于其各种组分赋予AD发作弹性的能力，我们测试了寡肽是否可以特异性地预防或减轻AD痴呆的临床前进展。我们还探索了寡肽发挥其生物活性的潜在机制。Oligopin在体外不仅抑制Aβ1-40和Aβ1-42的寡聚体形成，而且抑制tau蛋白的寡聚体形成。我们对体内代谢物蓄积的药代动力学分析鉴别出小鼠血浆中的Me-EC-O-β-葡糖苷酸、Me-（±）-C-O-β-葡糖苷酸、EC-O-β-葡糖苷酸和（±）-C-O-β-葡糖苷酸。这些代谢物主要是甲基化和葡萄糖醛酸化的C和EC结合物。进行的研究为设计未来的生物活性寡肽临床试验提供了必要的动力，以预防前驱和残留形式的AD。
Plant-derived polyphenolic compounds possess diverse biological activities, including strong anti-oxidant, anti-inflammatory, anti-microbial, and anti-tumorigenic activities. There is a growing interest in the development of polyphenolic compounds for preventing and treating chronic and degenerative diseases, such as cardiovascular disorders, cancer, and neurological diseases including Alzheimer’s disease (AD). Two neuropathological changes of AD are the appearance of neurofibrillary tangles containing tau and extracellular amyloid deposits containing amyloid-β protein (Aβ). Our laboratory and others have found that polyphenolic preparations rich in proanthocyanidins, such as grape seed extract, are capable of attenuating cognitive deterioration and reducing brain neuropathology in animal models of AD. Oligopin is a pine bark extract composed of low molecular weight proanthocyanidins oligomers (LMW-PAOs), including flavan-3-ol units such as catechin (C) and epicatechin (EC). Based on the ability of its various components to confer resilience to the onset of AD, we tested whether oligopin can specifically prevent or attenuate the progression of AD dementia preclinically. We also explored the underlying mechanism(s) through which oligopin may exert its biological activities. Oligopin inhibited oligomer formation of not only Aβ1–40 and Aβ1–42, but also tau in vitro. Our pharmacokinetics analysis of metabolite accumulation in vivo resulted in the identification of Me-EC-O-β-Glucuronide, Me-(±)-C-O-β-glucuronide, EC-O-β-glucuronide, and (±)-C-O-β-glucuronide in the plasma of mice. These metabolites are primarily methylated and glucuronidated C and EC conjugates. The studies conducted provide the necessary impetus to design future clinical trials with bioactive oligopin to prevent both prodromal and residual forms of AD.