基于肠道菌群、Aβ和Tau探讨槲皮素联合维生素D改善AD的机制研究

Alzheimer’s disease (AD) is an important public health problem, especially for the elderly in China. As yet, neither a satisfying therapy nor a preventative cure is available for AD. Evidence suggest that gut microbiota is involved in the pathogenesis and development of AD via multiple pathways. The prevalence of vitamin D deficiency is very high for middle-aged and aged people in our country. Quercetin (Q) is a kind of natural flavonoids. There is evidence suggest that 1) both Q and VD is protective against AD; 2) a potential combined effects exist between them; and 3) both could affect gut microbiota. However, currently, there is no evidence whether or not a combined effects exist for Q and VD in the modulation of AD pathology, if so, what is the potential role of gut microbiota? Pilot data from our laboratory suggest that combined effects might exist between Q and VD in regards to their effects on improving cognitive impairment in AD mice model. Consequently, this proposal is aimed 1) to explore whether quercetin combined with vitamin D could improve Aβ, tau pathology and cognitive function in 3×Tg-AD mice, and whether combined effects exist between them, as well as the potential involvement of gut microbiota via 16SrRNA sequencing and gut microbiota transplantation. 2) to explore how quercetin combined with vitamin D modulate Aβ and tau pathology via SH-SY5Y and hCMEC/D3 as models. Findings from this proposal will hold promise for identifying potential food bioactive molecules in the prevention and/or treatment of AD especially for middle-aged and aged people in our country.

AD是影响我国老年人群健康的重要公共卫生问题，目前尚无理想疗法。肠道菌群参与AD发生和进展。我国中老年人群维生素D（VD）缺乏十分严重。槲皮素（Q）属于天然黄酮类化合物。有证据表明Q和VD：①具有保护AD的作用；②可能存在联合作用；③可调节肠道菌群。目前尚无研究探讨Q和VD调节AD病理学是否有联合作用，及肠道菌群的可能参与。申请人预实验提示Q联合VD改善AD模型小鼠认知功能障碍可能存在联合作用。本课题拟：⑴以3×Tg-AD小鼠为模型探讨Q联合VD调节Aβ及Tau病理学、改善认知功能障碍是否有联合作用；通过肠道菌群16SrRNA测序和菌群移植实验，验证肠道菌群在联合干预改善AD中的作用。⑵以人骨髓神经母细胞瘤SH-SY5Y和人微血管内皮细胞hCMEC/D3为模型，探讨干预调节Aβ和Tau病理学的具体机制。研究结果为我国中老年人群以食物活性成分为基础的AD防治措施实施提供理论依据。

随着我国人口的快速老龄化，阿尔茨海默病（AD）的发病率和死亡率迅速上升，已成为城乡排名第五的死因，给个人、家庭和社会带来沉重的经济负担。膳食因素在防治AD中发挥重要作用。我国中老年人群维生素D缺乏十分严重，槲皮素属于天然黄酮类化合物。有证据表明槲皮素和维生素D具有保护AD的作用，且可能存在联合作用。因此探讨槲皮素联合维生素D对AD的影响及可能机制对AD的防控具有重要理论意义。. 我们分别以APP/PS1小鼠（10周龄）和ICR小鼠（12月龄）为模型，探讨不同维生素D状态下，槲皮素对认知功能的影响及可能机制。在APP/PS1AD模型鼠中，我们发现：槲皮素对AD的神经保护作用可能受机体维生素D状态影响，维生素D水平较低者可能是槲皮素补充获益最大的人群。槲皮素干预后小鼠认知功能的改善可能与以下过程有关：Aβ斑块和tau蛋白磷酸化的减少，神经炎症和BDNF水平的改善，海马组织中miR-26a和miR-125b水平的降低和miR-132表达水平的增高，以及包括Facklamia和Aerococcus在内的肠道微生物多样性的提升。在ICR小鼠中，我们发现：维生素D缺乏导致肝脏节律紊乱，槲皮素补充改善维生素D缺乏相关的肝脏节律紊乱；但是干预对下丘脑节律蛋白及认知功能并无显著影响。鉴于脂肪组织分泌的脂肪因子：脂联素和瘦素也与认知功能存在密切关系，作为扩展，我们采用荟萃分析的方法探讨了包括槲皮素在内的黄酮类化合物补充对血清脂联素和瘦素影响的随机临床对照研究，发现黄酮类化合物具有升高血清脂联素、降低瘦素的作用。这提示未来可以从脂肪组织-大脑交互的角度探讨槲皮素改善认知功能的可能机制。. 该项目整体提示槲皮素对认知功能的保护作用可能与机体维生素D状态有关，未来应通过随机临床对照研究的手段探讨不同维生素D状态下，槲皮素改善认知功能的可能性及有效剂量，从而为以膳食为基础的AD防治措施实施提供理论依据。.