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

认知能力下降和大脑老化的其他症状是由细胞之间的连接丧失引起的，导致通信失败，即神经网络功能障碍。调整人类饮食，以提供特定的耐受性良好的保护成分，无论是在食物中，作为营养保健品或作为传统药物的仿制品，都是一种具有潜在吸引力的具有成本效益的策略，可以保持这些连接，从而促进健康的大脑衰老，特别是在痴呆症的长期阶段。我们的研究目标是确定最有效的饮食分子，为了实现这一目标，我们正在研究与年龄相关的认知能力下降的分子机制，同时我们正在测试以饮食多酚为重点的天然产品。像许多其他研究实验室一样，我们一直在小鼠模型和小鼠细胞中进行几乎所有的工作，但现在认为未来的研究在更相关的条件下在人类细胞中进行测试对该领域至关重要。部分原因是出于对使用啮齿动物的伦理考虑，但也是由于小鼠和人类对饮食干预的反应方式存在明显的物种特异性差异。因此，只有通过在人体细胞中采用新的方法，我们才能真正相信所获得的信息可以转化为改善人类健康。将我们的研究转移到人类细胞对我们来说是一个重大的挑战，因为在实验室中培养人类脑细胞，特别是神经元，一点也不简单，而且这些细胞是否可以用来模拟与年龄相关的神经网络功能障碍还没有确定。因此，我们建议在我们的方法中做出一步改变，从人类胚胎干细胞而不是小鼠中培养神经元，并将其与最先进的微电极阵列技术相结合，以记录这些细胞之间形成的神经元网络。我们将通过引入已知在衰老的大脑中积累的有毒蛋白质来模拟与年龄相关的变化。如果成功，这将为研究大脑衰老的分子机制提供一个先进的人类细胞系统，一个更生理学上相关的模型来测试饮食多酚，最终我们预计将在这一研究领域显著取代小鼠模型。

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.