Implementing an MEA platform in human neurones for studying age-related neural network dysfunction and testing dietary interventions

Cognitive decline and other symptoms of brain ageing are caused by a loss of connections between cells resulting in communication failure known as neuronal network dysfunction. Adaptation of the human diet to deliver specific well-tolerated protective components, either in food, as nutraceutical supplements or as mimics of conventional medicines, is a potentially attractive cost-effective strategy for preserving these connections thus promoting healthy brain ageing, particularly during the long phases of dementia. Our research goal is to identify the most effective dietary molecules and to achieve this aim, we are investigating the molecular mechanisms underpinning age-related cognitive decline and in parallel we are testing natural products with a focus on dietary polyphenols. Like many other research laboratories we have been undertaking almost all our work in mouse models and in mouse cells but it is now viewed as critical to the field that future studies are tested under more relevant conditions in human cells. This is partly because of ethical concerns regarding the use of rodents but is also due to clear species specific differences in the way that mice and humans respond to dietary interventions. It is therefore, only through adopting new approaches in human cells that we can have any real confidence that information gained can be translated into improvements in human health. Moving our research into human cells is a significant challenge for us because growing human brain cells, specifically neurones, in the laboratory is not at all straightforward and whether these cells can be used to model age-related neuronal network dysfunction has not been established. We therefore propose to make a step change in our approach by growing neurones from human embryonic stem cells rather than from mice, and combining this with state-of-the-art microelectrode array technology to record the neuronal network that forms between these cells. We will mimic age-related changes by introducing toxic proteins that are known to accumulate in the ageing brain. If successful this will deliver an advanced human cell system for studying the molecular mechanisms of brain ageing, a more physiologically relevant model for testing dietary polyphenols and ultimately we anticipate will lead to the significant replacement of mouse models for this research area.

Brain network alterations in the prefrontal cortex and aberrant entorhinal cortex-hippocampal connectivity occurs decades before the symptomatic onset of dementia. It can thus be speculated that early brain network dysfunction not only contributes to cognitive dysfunction but also to the progression of brain ageing. Epidemiology has strongly suggested that dietary polyphenol intake can be inversely related both to subjective age-related cognitive decline and to the risk of developing dementia but the precise functional forms of bioavailable polyphenols need to be identified and their mechanisms of action firmly established. Species specific differences between the mouse and human polyphenol metabolomes and diversity in their response to polyphenols has hindered progress necessitating a move from mouse models into more relevant human systems to enhance translatability. We therefore propose to replace our existing mouse models with neurones derived from human embryonic stem cells and use these cells to monitor neural network activity by adopting multi-well plate microelectrode array technology. For this proof-of-principle study age-related changes will be mimicked by expression of tau and validation as a screening platform will be established by testing the activity of known bioactive polyphenol metabolites. If successful this will deliver an advanced human cell system for studying the molecular mechanisms of brain ageing, a more physiologically relevant model for testing dietary polyphenols and ultimately we anticipate will lead to the significant replacement of mouse models for this and related research areas.