Identification of the neuronal receptor for the cognitive-enhancing soluble klotho ligand

衰老是认知能力下降的主要危险因素，包括学习和记忆问题。在这个项目中，我们将专注于抗衰老蛋白质，klotho，它具有增强认知能力的特性。Klotho增强神经细胞的功能，特别是学习和记忆所需的突触的变化。此外，klotho保护神经细胞免受氧化损伤，这种损伤在老年大脑中增加。klotho的这些认知增强特性是通过klotho与神经细胞表面上的未知受体相互作用来介导的。我们假设人类神经细胞上klotho受体的鉴定和表征将为认知增强策略提供新的机会，以对抗与年龄相关的认知功能障碍。该项目的目标是采取必要的后续步骤，通过以下方式探索klotho的认知增强潜力：1）识别人类神经细胞表面上的klotho受体; 2）验证细胞和脑组织中的klotho受体; 3）确定klotho受体如何与神经细胞功能的有益变化联系起来。我们将使用一系列最先进的生物化学和细胞生物学方法来解决这些目标，并将我们的发现与通过使用人类干细胞衍生的神经元和死后人脑材料在人脑中观察到的变化联系起来。klotho受体的鉴定将为新的药理学方法开辟道路，以模拟klotho在年龄相关的认知功能障碍中的活性。

Ageing is the main risk factor for cognitive decline, including problems with learning and memory. In this project we will focus on the anti-ageing protein, klotho, which has cognitive-enhancing properties. Klotho enhances the function of nerve cells, particularly the changes in synapses that are required for learning and memory. In addition, klotho protects nerve cells against oxidative damage which increases in the aged brain. These cognitive-enhancing properties of klotho are mediated by klotho interacting with an unknown receptor on the surface of nerve cells. We hypothesise that identification and characterisation of the receptor for klotho on human nerve cells will provide new opportunities for cognitive-enhancing strategies to combat age-related cognitive dysfunction. The objectives of this project are to take the essential next steps in exploring the cognitive-enhancing potential of klotho by: 1) identifying the receptor for klotho on the surface of human nerve cells; 2) validating the receptor for klotho in cells and brain tissue; and 3) determining the how the klotho receptor links to the beneficial changes in nerve cell function. We will use a range of state-of-the-art biochemical and cell biological approaches to address these objectives, and will link our findings to changes seen in the human brain by using human stem cell-derived neurons and post mortem human brain material. Identification of the klotho receptor will open the way to novel pharmacological approaches to mimic klotho activity in age-associated cognitive dysfunction.