An interrogation of synaptic dysfunctions arising from human cognitive disease gene mutations using opto-physiological and neurochemical strategies.

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More than 50 million people in the world are living with dementia today, and approximately £550 billion is spent each year on their health and social care. Alzheimer's disease is the most common type of dementia, but current treatments have very little effect on the disease, and the need for new medicines is urgent. Designing effective new medicines will require a greater understanding of why and how Alzheimer's disease develops, something that currently remains largely obscure. We do know that the very first stages of Alzheimer's disease involve changes to nerve cells in the brain, and in particular now they communicate with each other, and that these changes seem to be important in driving forward the progression of the disease. However, how the changes come about is largely a mystery. What is clear is that alterations in the way specific identified proteins behave within nerve cells are closely associated with the appearance of the disease in humans. As it is not possible to manipulate these proteins directly in humans an alternative approach is to manipulate the expression in animals. For us to be confident that such studies are informative in helping understand the basis of human disease it is essential that the animal models accurately capture the features of the human disease. For this reason a key component of the work will be the development of robust dementia and intellectual disability-related mouse models that closely replicate the neuropathology and disease trajectories associated with dysfunctional cognition in humans. With such mice it is then possible to perform quite specific experiments that seek to identify the changes that are driving the disease. Said another way, in living mice it is possible to examine the progression of the disease, along with the changes at and between nerve cells, in order to identify the cause of the cognitive decline? There are however other important experimental elements that need to be in place in order that this approach can be successful implemented. One is a robust method with which to detect any changes that have occurred. For this probes must be developed that are able to measure such changes. The second is a method where the output from the probes can be measured without disrupting the brain of the animal. Clearly disruption of the brain would compromise the study as it would become challenging to determine whether the disease or the disruption was responsible for the cognitive decline. For these reasons the project will to be conducted by a team of scientists from Japan and the UK who have specific expertise in each of the key areas: the development of new mouse models, the development of new probes for the detection of changes within the animal's nervous system and the development of innovative imaging technologies with which to image cells with little or no disruption to the nervous system.