Processes controlling the communication between brain cells in Alzheimer’s disease and Down’s syndrome

Scientific title: Analysis of changes in protein SUMOylation in Alzheimer’s and Down’s syndrome brain: implications for reducing impaired AMPAR trafficking and synaptic dysfunction

Type of project: PhD studentship - Caroline Binda, co-supervised by Dr Kevin Wilkinson, Professor Seth Love and Professor Pat Kehoe

What do we already know?

The brain is composed of billions of nerve cells which communicate by sending out chemical signals called neurotransmitters. Neurotransmitters travel across the gaps between cells and interact with receptor proteins on other nerve cells to send them a signal – this junction is called a synapse. AMPA receptors are found at synapses and are involved in receiving fast communication signals in the brain. In the early stages of dementia this signalling between cells goes wrong because AMPA receptors are not correctly positioned to receive neurotransmitter signals.

In normal brain cells, AMPA receptor numbers can be increased and decreased depending on the incoming signals, but in Alzheimer's disease and Down's syndrome too many receptors are removed and not replaced, leading to degeneration of synapses and eventually death of cells in the brain. Those with Down’s syndrome have a tendency to develop dementia at a younger age than the general population.

What is this project trying to find out?

This project aims to investigate what goes wrong with the processes controlling AMPA receptors in dementia, particularly looking at SUMOylation. SUMOylation is the process by which the small protein SUMO is attached to target proteins to change their characteristics. It has a role in controlling the location of AMPA receptors at synapses, and has been implicated in many diseases including cancer, stroke and Parkinson's disease.

How is this being done?

Post-mortem brain samples will be used from Alzheimer's disease and Down's syndrome patients, together with healthy brain samples from subjects of a similar age. The changes in SUMOylated proteins will be profiled using a technique called monoclonal antibody-based affinity chromatography, where proteins that have SUMO attached can be isolated from other proteins. The proteins isolated can then be analysed to see how the level of SUMOylation changes, and if there are any changes in which proteins are SUMOylated in diseased brains.

Why is it important?

If we know some of the signalling proteins or pathways which are disrupted in dementia, this will allow them to be specifically targeted by therapies which may help to prevent synapse degeneration and cell loss in the brain.

Please click here for more information about the work of Professor Jeremy Henley.