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

目前，英国有80万人患有痴呆症，预计到2025年将增加到100万人。据估计，77%的老年人在养老院患有痴呆症。阿尔茨海默氏病（AD）是最常见的形式，其特征在于记忆丧失、情绪变化以及沟通和推理困难。个体的AD风险由生活方式（运动，吸烟，饮食等）和遗传因素决定。我们的基因（DNA）中的变异携带了体内所有蛋白质制造所需的信息，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疾病的风险，如AD。APOE基因的变异导致蛋白质的三种可能版本，即E2，E3或E4。我们每个基因都有两个拷贝，与最常见的APOE 3/E3（60%英国人口）相比，APOE 3/E4（25%英国人口）或APOE 4/E4（2%英国人口）的AD风险增加了3倍和15倍。在细胞、小鼠和人类研究中，我们和其他人已经证明，与APOE 4基因型相关的风险增加的很大一部分可能是由于（神经）炎症和氧化应激增加。在AD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）。某些膳食成分，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和改善认知。尽管这些饮食成分的有益影响与APOE 4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APOE 4携带者患痴呆症风险的能力尚不清楚。此外，考虑到DHA和黄烷醇对大脑生物学有一些不同的影响，我们假设这两种成分同时喂养的效果比单独喂养的效果更大。简而言之，我们将在表达人类APOE 3或APOE 4基因的小鼠中进行喂养研究。成年APOE 3或APOE 4小鼠将喂食对照食物饮食、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16周。每4周使用径向臂水迷宫评估一次动物的脑功能，该迷宫通常用于评估不同形式的记忆。在喂养期结束时，将处死动物，并分析脑组织中调节脑炎症和氧化状态的一系列因素，沿着DHA（和其他脂肪），黄烷醇和它们产生的一系列化合物的水平。此外，动物的大脑将被染色的“染料”，使可视化（使用先进的显微镜技术）的神经元和功能，生长和修复的标志物。从科学的角度来看，概述的工作预计将显着推进目前的理解APOE基因型和饮食成分对认知能力和潜在的生物学机制的相互影响。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，特别是在大型“高危”APOE 4人群亚组中。这将与老年人生活质量方面的相当大的好处有关，并减少与痴呆症相关的不断增加的NHS支出。

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.