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

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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.