Cellular and circuit mechanisms of Alzheimer's disease

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Alzheimer's disease (AD) is the public health and scientific challenge of our age. The disease is characterised by the presence of abnormal deposits of Abeta and tau proteins in the brain and a loss of nerve cells in regions critical for learning, memory and cognition. The overall aim of my work is to understand why nerve cells, and the brain networks in which they reside, become faulty in AD and lead to tragic changes in how patients are able to think, act and feel.In pursuit of this aim, my fellowship has thus far led to important insights into how toxic proteins that build up in the brains of AD patients affect specific brain cells and networks, and this has opened up new targets for potential treatments. As part of this, my laboratory has established state-of-the-art tools that allow recordings of brain cell and network activity with very high precision, and which can now be used to study how brain cells and networks interact across distant regions of the brain, including those located deep in the brain which have been traditionally difficult to reach and record at the same time as those in shallower locations. This is important, as recent work has suggested that deeper brain regions also show the build-up of toxic proteins, communicate differently in AD, and are ever more thought to play a key role in shaping mental abilities such as memory. In order to build on my work over the last three years, this fellowship renewal proposes to exploit and further develop these technologies and gather cutting-edge experimental data in disease models that will allow a brain-wide model of how brain cells and networks are affected by AD. This research will significantly move forward our understanding of how microscopic changes across the AD brain, such as the build-up of toxic proteins and their effect on brain cells, are linked to changes at the 'real-world' level, such as poor memory and altered behaviour, which is currently unclear. This has the considerable potential to offer much needed signatures of disease stage and sensitive read-outs of treatment outcomes, so that treatments can be given at the right time to the right patients and judged on their ability to bring about meaningful real-world benefits to the patient. This work will therefore draw and build upon the significant knowledge and technical advances recently made in my laboratory. It will allow my research to take the next major step forward to understand the impact of AD on the whole brain and lead to important outcomes that are urgently required to tackle this devastating and all too common disease.