茶多酚对改善认知功能和预防老年痴呆的作用及其抗氧化机制的研究

On the basis of the current development of the research and knowledge on dementia prevention and our previous findings, this proposed project aims to investigate the effect of tea polyphenols on improving cognitive function and preventing dementia through antioxidant mechanism. To reach the goal, four-dimension research including a population-based observational study, in-vivo and in-vitro experiments and a population-based intervention study will be carried out. The population observation is based on a large community-based cohort study of the Swedish elderly people with 9-year follow-up (N=3363 aged ≥60, including 550 people received brain MRI scans), which will be used to examine the associations of polyphenol-rich foods (including green tea drinking) with cognitive function, dementia risk and structural brain changes. In the in-vivo and in-vitro experiments, the effects of tea polyphenols on oxidative stress in Alzheimer’s disease (AD) cell model and animal model, learning and memory abilities in mice and the expression of AD-related genes will be assessed to investigate its antioxidant pathway. The population-based interventional study, which is a double-blind randomized clinical trial, will enroll 1200 participants (including 200 who will receive brain MRI scans) aged 60-70 years at high dementia risk using CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) Dementia Risk Score ≥6. The participants will be randomly assigned (1:1) into two groups (600 in the tea polyphenols intervention group and 600 in the placebo group), and followed-up for 24 months. After the follow-up, the effect of tea polyphenols on cognitive function, dementia risk and brain MRI changes will be further assessed. This project will provide not only the evidence for the etiology of AD, also the opportunity to bridge the collaboration between Tianjin Medical University and Karolinska Institutet, more importantly, the new avenue for the prevention and treatment of dementing disorders.

根据国内外研究现状、相关理论以及前期研究基础, 本项目通过人群观察、细胞模型、动物模型和人群干预四维设计开展茶多酚通过抗氧化机制改善认知功能和预防老年痴呆的研究。人群观察研究采用社区为基础的瑞典老年人的定群研究 (9年随访,n=3363,550人接受了脑MRI扫描), 探讨多酚食物摄入与认知功能、老年痴呆及脑MRI改变的关系。通过研究茶多酚对AD细胞模型和动物模型氧化应激的调控作用、对小鼠学习记忆力的改变以及对AD发病相关基因表达的影响,明确茶多酚通过抗氧化途径影响AD发病的作用及其剂量。人群干预研究将筛选老年痴呆高危人群1200人 (200人进行脑MRI扫描), 按1:1随机分为茶多酚干预组和安慰剂组观察24个月, 进一步证实茶多酚改善认知功能、预防老年痴呆以及大脑MRI显示的神经保护作用。该项目的实施将为老年痴呆的防治开辟新的途径, 并为AD的发病机制提供依据, 同时也将架起中瑞合作的又一座桥梁。

社会人口老龄化趋势日渐加重，老年痴呆病例在不断上升，给患者的家庭和社会带来沉重的负担。迄今为止尚无有效的老年痴呆治疗方法，因此深入探讨老年痴呆的发病机制和积极寻求经济有效的预防方法具有重要的公共卫生学意义。本项目通过瑞典人群观察性研究、细胞实验、动物实验及中国人群干预研究四维设计开展茶多酚通过抗氧化途径对改善认知功能和预防老年痴呆的作用及其机制的研究。.瑞典人群前瞻性队列研究结果表明，富含多酚的北欧审慎膳食模式与认知功能下降延缓[β=0.24，95%置信区间（CI）：0.18−0.30]和认知功能减退风险降低（风险比为0.18，95%CI：0.08−0.39）有关；该膳食模式也与较高的健康（无痴呆/失能）生存的概率有关（风险比为1.02，95%CI：1.01−1.02）。.细胞和动物实验结果显示，茶多酚可激活谷胱甘肽（GSH）、超氧化物歧化酶（SOD）和过氧化氢酶（CAT）对抗β-淀粉样蛋白1-42引发的氧化应激，抑制半胱氨酸蛋白酶-3（caspase-3）和核因子κB（NF-κB）的活化，防止神经元凋亡。茶多酚可减轻大脑β-淀粉样蛋白斑块沉积，下调淀粉样蛋白前体蛋白（APP）表达，并通过下调β-淀粉样蛋白前体裂解酶1和早老蛋白-1表达，抑制APP病理过程，减少淀粉样变形成，起到神经保护作用。.天津市社区为基础的干预研究结果显示，有轻度认知障碍的研究对象持续摄入茶多酚（约含表没食子儿茶素没食子酸酯800mg/天）24个月后，其认知功能得分（蒙特利尔认知评估量表和韦氏量表得分）、总脑容量、白质、灰质和脑脊液体积均未发生显著性的下降，P值均大于0.05。此外，人群血清caspase-3和CAT水平与蒙特利尔认知功能评分之间存在正相关（r=0.46，P=0.008；r=0.45，P=0.032），茶多酚干预后血清SOD、CAT和谷胱甘肽过氧化物酶水平显著上升（t分别为4.19、3.75和3.26，P值均＜0.05）、NF-κB水平发生下降（t=-3.48，P=0.002）。.以上四维研究结果一致显示茶多酚可通过抗氧化途径改善认知功能，从而为老年痴呆的早期预防提供了依据。基于本项目，该课题组累计发表SCI论著20篇、综述1篇，培养研究生15名（博士生研究生7名、硕士研究生8名），并参加国内外学术合作交流10余人次。