Enhancement of learning and memory by flavonoids

Representing one of the most important lifestyle factors, diet can strongly influence the incidence of cardiovascular disease and neurodegenerative diseases and thus a healthy diet is crucial for healthy ageing. Various bioactive constituents of certain foods and beverages, in particular a class of compounds called flavonoids, have generated interest over the last few years. Recent dietary intervention studies, in particular those using wine, tea, cocoa or blueberries, have begun to demonstrate beneficial effects on the function of blood vessels and on mental performance. While such foods and beverages differ greatly in chemical composition, nutrient content and calories per serving, they have in common that they are amongst the major dietary sources of two groups of flavonoids known as anthocyanins and flavanols. Dietary supplementation studies in humans and animal models using foods or extracts rich in these flavonoids have indicated that they possess an ability to enhance memory and learning. It is thought that they may do this by 1) protecting vulnerable brain cells, 2) enhancing existing brain cell function, 3) stimulating brain cell regeneration, or 4) triggering the growth of new brain cells and/or new blood vessels. Building on existing human and animal work conducted in our laboratory, this multidisciplinary study is designed to determine how specific flavonoids may enhance memory and learning by focussing on their potential to stimulate the growth of new neurons and blood vessels, and the molecular events which determine these changes. The study will also provide crucial information on the ability of flavonoid-rich foods to produce improvements in memory and learning in human older adults using both behavioural and state-of-the-art, brain imaging (fMRI) techniques. The outcomes of this proposal have implications for exploiting the potential beneficial health effects of flavonoid components of the diet, particularly with relation to counteracting the decline in human learning and memory which is associated with normal and abnormal ageing. If we are able to determine which flavonoids are the most beneficial, and how and where they work in the brain, this will help us develop future strategies to maximise these dietary agents in our foods, for example, by developing plants or novel functional food products with high levels of specific flavonoids. In addition, specific dietary advice on food consumption will be improved, as will guidelines to prevent the indiscriminate marketing of food supplements on the basis of putative protective effects. The proposal will broaden understanding of the role that diet plays in the prevention of human brain ageing and the enhancement of a range of cognitive abilities (e.g., spatial memory, long-term memory). The study will also provide the background for new and promising preventive treatments for tackling cognitive decline. The results of this study therefore have important implications for an ageing population where an increase in healthy ageing is greatly desired. Moreover, the potential benefits in terms of quality of life are relevant to the population as a whole, as are the potential savings in health care costs.

Dietary derived flavonoids have been shown to protect against age-related cognitive decline in animals and humans. These beneficial effects have been attributed to their potential to act selectively within neuronal signalling pathways that regulate neuronal viability, morphology, neurogenesis and angiogenesis. This proposal is designed to unravel the mechanisms by which flavonoids and flavonoid-rich foods influence learning and memory in animals and humans. In animal investigations, we will underpin changes in our behavioural measures of learning and memory with state-of-the-art measurements of neuronal morphology, angiogenesis and neurogenesis. This will be achieved via the reconstruction of whole neuron and vessel structure from z-stacks of confocal microscope-captured images (Leica TCS SP2 AOBS) using neuroanatomical analysis (Neurolecida; MBF Bioscience). The cellular and molecular basis of morphological changes will be addressed using: 1) targeted gene arrays for neurogenesis, neurotrophins and receptors; 2) Western immunoblotting of relevant signalling pathways, notably mitogen-activated protein kinase (MAPK), cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF) and downstream pathways involved to de novo protein synthesis (mTOR, Arc.Arg3.1 etc); 3) Immunohistochemical analysis of NMDA and AMPA- receptor density and neurogenesis. We will also perform a randomised, double blind, cross-over human intervention study using a group of healthy older adults. The study will employ an analytically well characterised food containing a defined and standardised amount of flavanols (495mg) and a macro- and micronutrient-matched control that contains a low amount of flavanols (23 mg). The success of this intervention will be assessed through changes in neural activity (BOLD) using a state-of-the-art fMRI scanning technique, as well as by performance on a broad range of cognitive tests and measurements of serum BDNF.