Klotho as a therapeutic target for Alzheimer's disease

Currently there are nearly 1 million people living with dementia in the UK and this number is set to double within a generation. Alzheimer's disease is the commonest form of dementia for which currently there is no means of stopping or even slowing the disease. The major symptom of Alzheimer's disease is cognitive dysfunction, often seen as a loss of memory, caused by changes in nerve cell function. In this project we will focus on the anti-ageing protein, klotho, which has cognitive-enhancing properties. Klotho enhances the function of brain cells, reversing the Alzheimer's disease related changes in nerve cells that are required for learning and memory. In addition, klotho protects cells against oxidative damage which increases in the Alzheimer's disease brain. These cognitive-enhancing properties of klotho are mediated by the soluble form of klotho interacting with an unknown receptor on the surface of nerve cells in the brain. We hypothesise that identification and characterisation of the cellular receptor for soluble klotho, and its downstream signalling pathways, will provide new opportunities for cognitive-enhancing strategies to combat Alzheimer's disease. Thus the objectives of this project are to take the essential next steps in exploring the cognitive-enhancing potential of soluble klotho by: 1) identifying and characterising the receptor for soluble klotho on the surface of brain cells; and 2) determining the soluble klotho-induced signalling pathways that link to changes in nerve cell function and protection against oxidative damage. We will use a range of state-of-the-art biochemical and cell biological approaches (including receptor identification, mass spectrometry, bioinformatics, immunofluorescence microscopy, membrane potential assays) to address these objectives, and will link our findings to changes seen in the human brain by using human induced pluripotent stem cells and post mortem human brain material. Identification of the receptor for soluble klotho and its downstream signalling pathways will open the way to novel pharmacological approaches to mimic klotho activity as a potential therapeutic approach in Alzheimer's disease.