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

认知衰退和大脑老化的其他症状是由细胞之间失去连接导致的通信故障引起的，称为神经元网络功能障碍。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，作为营养补充剂或作为传统药物的仿制品，是一种潜在的具有吸引力的成本效益战略，可以保留这些联系，从而促进健康的大脑老化，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，并实现这一目标，我们正在研究与年龄相关的认知能力下降的分子机制，同时我们正在测试天然产品，重点是饮食多酚。像许多其他研究实验室一样，我们几乎所有的工作都是在小鼠模型和小鼠细胞中进行的，但现在人们认为，未来的研究在更相关的条件下在人类细胞中进行测试是至关重要的。这在一定程度上是因为对使用啮齿动物的伦理担忧，但也是因为老鼠和人类对饮食干预的反应方式存在明显的物种差异。因此，只有通过在人类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巨大的挑战，因为在实验室中培养人类脑细胞，特别是神经细胞，并不是一帆风顺的，这些细胞是否可以用来模拟与年龄相关的神经元网络功能障碍还没有确定。因此，我们建议对我们的方法进行一步的改变，从人类胚胎干细胞而不是小鼠培养神经元，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老化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，为测试饮食多酚提供一个更具生理学相关性的模型，最终我们预计将导致这一研究领域的小鼠模型的重大替代。

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.