Enhanced cognition through dietary modulation of neuroinflammation in high risk APOE4 carriers

通过膳食调节高危 APOE4 携带者的神经炎症来增强认知能力

• 批准号: BB/M004449/1
• 负责人: Anne-Marie Minihane
• 金额: $ 55.6万
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM004449%2F1
• 关键词: Enhanced; cognition; through; dietary; modulation

Currently 800,000 individuals in the UK have dementia, with a predicted rise to one million sufferers by 2025. An estimated 77% of those in elderly care homes suffer from dementia. Alzheimer's disease (AD), which is characterised by a loss of memory, mood changes, and communication and reasoning difficulties, is the most common form. An individual's risk of AD is determined by both lifestyle (exercise, smoking, diet etc) and genetic factors. Variations in our genes (DNA), which carry the information necessary for the manufacture of all proteins in the body, can affect both the structure of the protein or the levels produced. This may subsequently change body metabolism and risk of diseases such as AD. Variation in the APOE gene results in three possible versions of the protein, namely E2, E3 or E4. We all have two copies of each gene and those of us who are APOE3/E4 (25% UK population) or APOE4/E4 (2% UK population) are at 3- and 15-fold increased risk of AD compared to those with the most common APOE3/E3 (60% UK population). Furthermore APOE4 carriers develop the disease at a much younger age.In cell, mice and human studies, we and others have demonstrated that a large component of the increased risk associated with an APOE4 genotype is likely to be due to increased (neuro)inflammation and oxidative stress. In AD, neuroinflammation and oxidative stress reduce the function of brain cells (neurons), and in particular the end region (the synapsis) which pass on signals to adjacent neurons. Certain dietary components such as DHA (a fish oil fatty acid) and flavanols (plant derived compounds found in cocoa, berries and tea), have been shown to reduce inflammation and improve cognition. Although there is considerable 'overlap' between the beneficial impact of these dietary components and the negative impact of the APOE4 genotype on brain function, surprisingly the ability of DHA and flavanols to reduce the risk of dementia in APOE4 carriers is unknown. Furthermore given that DHA and flavanols have some distinct effects on brain biology, we hypothesise that the effect of the two components fed simultaneously will have a greater impact than either fed separately.In brief, we will carry out a feeding study in mice which express either the human version of the APOE3 or APOE4 gene. Adult APOE3 or APOE4 mice will be fed a control chow diet, a high fat diet (HFD, similar to a human diet), HFD+DHA, HFD+flavanols, or HFD+DHA and flavanols, for 16 weeks. Brain function in the animals will be assessed every 4 weeks using a radial arm water maze, which is commonly used for the assessment of different forms of memory. At the end of the feeding period, the animals will be sacrificed and the brain tissue analysed for a range of factors which modulate brain inflammation and oxidative status, along with the levels of DHA (and other fats), flavanols and a range of compounds they produce. In addition the brains of the animals will be stained with 'dyes' enabling the visualisation (using sophisticated microscopy techniques) of markers of neuronal and function, growth and repair.From a scientific point of view the outlined work is predicted to significantly advance current understanding of the interactive impact of APOE genotype and dietary components on cognitive abilities and the underlying biological mechanisms. From a public health view-point we aim to identify targeted dietary strategies, which will promote healthy brain ageing, in particular in the large 'at-risk' APOE4 population subgroup. This would be associated with considerable benefit with respect to quality of life in the elderly, and reductions in the ever increasing NHS spent associated with dementia.

目前，英国有80万人患有痴呆症，预计到2025年，这一数字将上升到100万。据估计，住在养老院的人中有77%患有痴呆症。阿尔茨海默病（AD）是最常见的一种，其特征是记忆丧失、情绪变化、沟通和推理困难。个人患阿尔茨海默病的风险取决于生活方式（运动、吸烟、饮食等）和遗传因素。我们的基因（DNA）携带着制造体内所有蛋白质所必需的信息，它的变异可以影响蛋白质的结构或产生的水平。这可能随后改变身体代谢和AD等疾病的风险。APOE基因的变异导致了该蛋白的三种可能版本，即E2、E3或E4。我们每个人都有两个基因副本，APOE3/E4（25%的英国人）或APOE4/E4（2%的英国人）的人患AD的风险是最常见的APOE3/E3（60%的英国人）的3倍和15倍。此外，APOE4携带者发病的年龄要小得多。在细胞、小鼠和人类研究中，我们和其他人已经证明，APOE4基因型增加的风险的很大一部分可能是由于（神经）炎症和氧化应激的增加。在阿尔茨海默病中，神经炎症和氧化应激降低了脑细胞（神经元）的功能，特别是将信号传递给相邻神经元的末端区域（突触）的功能。某些饮食成分，如DHA（一种鱼油脂肪酸）和黄烷醇（可可、浆果和茶中发现的植物衍生化合物），已被证明可以减少炎症，提高认知能力。尽管在这些饮食成分的有益影响和APOE4基因型对脑功能的负面影响之间存在相当大的“重叠”，但令人惊讶的是，DHA和黄烷醇降低APOE4携带者患痴呆风险的能力尚不清楚。此外，鉴于DHA和黄烷醇对大脑生物学有一些不同的影响，我们假设同时饲喂这两种成分的影响将比单独饲喂的影响更大。简而言之，我们将在表达人类APOE3或APOE4基因的小鼠中进行喂养研究。成年APOE3或APOE4小鼠将被喂食对照饲料、高脂肪饮食（HFD，类似于人类饮食）、HFD+DHA、HFD+黄烷醇或HFD+DHA和黄烷醇，为期16周。研究人员将每4周使用径向臂水迷宫对这些动物的脑功能进行评估，这种方法通常用于评估不同形式的记忆。在喂养期结束时，动物将被处死，并对脑组织进行分析，以确定一系列调节脑部炎症和氧化状态的因素，以及DHA（和其他脂肪）、黄烷醇及其产生的一系列化合物的水平。此外，动物的大脑将被染色，使神经元和功能、生长和修复的标记物可视化（使用复杂的显微镜技术）。从科学的角度来看，预计概述的工作将显著推进目前对APOE基因型和饮食成分对认知能力及其潜在生物学机制的相互影响的理解。从公共卫生的角度来看，我们的目标是确定有针对性的饮食策略，这将促进健康的大脑衰老，特别是在大的“风险”APOE4人群亚群中。这将对老年人的生活质量带来相当大的好处，并减少与痴呆症相关的不断增加的NHS支出。

项目成果

The Influence of APOE Genotype, DHA, and Flavanol Intervention on Brain DHA and Lipidomics Profile in Aged Transgenic Mice.

• DOI: 10.3390/nu15092032
• 发表时间: 2023-04-23
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Martinsen A;Saleh RNM;Chouinard-Watkins R;Bazinet R;Harden G;Dick J;Tejera N;Pontifex MG;Vauzour D;Minihane AM
• 通讯作者: Minihane AM

The effect of dietary fish oil on weight gain and insulin sensitivity is dependent on APOE genotype in humanized targeted replacement mice.

• DOI: 10.1096/fj.201600921rr
• 发表时间: 2017-03
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Slim KE;Vauzour D;Tejera N;Voshol PJ;Cassidy A;Minihane AM
• 通讯作者: Minihane AM

Neuroinflammatory processes in cognitive disorders: Is there a role for flavonoids and n-3 polyunsaturated fatty acids in counteracting their detrimental effects?

• DOI: 10.1016/j.neuint.2015.08.004
• 发表时间: 2015-10
• 期刊: Neurochemistry International
• 影响因子: 4.2
• 作者: Dr David Vauzour;Anneloes Martinsen;S. Layé