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

点击翻译按钮获取中文摘要

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.