Identifying novel strategies to restore the microglial homeostatic phenotype and modulate neuroinflammation

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There is currently no cure for dementias, a group of diseases associated with degeneration of the brain and a reduced ability to think, remember or perform tasks. Alzheimer's disease (AD), is the commonest type and collectively they cause a huge financial and emotional burden to society. Failure of several clinical trials for AD points to a need for alternative and innovative approaches. Strong scientific evidence has indicated that a type of brain immune cell called microglia is involved in the initiation and progression of AD. The overarching aim of this project is to identify novel mechanisms to inhibit the progression of AD and other dementias by preventing the harmful changes that occur in microglia that are associated with disease. Microglia are one of a group of different cell types that help support the function of the nerve cells or neurons in the brain. The coordinated interaction of these different cell types is vital for the brain to function correctly. As immune cells, microglia respond to infection in a process called activation. Controlling microglial activation is vitally important because if microglia become incorrectly activated they can start to attack the neurons, something which is thought to happen dementia. In animal models of AD as well as in human AD, the incorrectly activated microglia change their shape and stop making healthy proteins. They also over-react to situations which may add to the disease that is already present. Understanding how microglia become incorrectly activated is therefore critical in finding new treatments for disease because if we can block or reverse the incorrect activation it may improve or prevent disease.Previously it was difficult to study microglia, as microglia become activated and change their properties as soon as they are taken out of the brain. To tackle this technical difficulty, we collaborated with bioinformaticians and invented a novel system in which the incorrect activation of microglia can be studied in the laboratory. Using this novel system, we can grow neurons, astrocytes (another type of brain cell) and microglia together in a dish so that they work together in a similar way to how they do in the brain. We then can study the interactions between these different brain cells in detail. We have discovered that neurons and astrocytes work together to release components that maintain microglial healthy properties and prevent their incorrect activation. This project aims to work out exactly what specific components released by neurons and astrocytes that are responsible for keeping microglial healthy properties and prevent their incorrect activation in order to develop new treatments for disease. We will also use this novel system to test a library of 4000 drugs already known to be safe for use in humans to look for those that maintain microglial healthy properties and prevent their incorrect activation, in order to work out the mechanisms to reveal novel therapeutic targets. This repurposing of known drugs accelerates the translation of these from bench to bedside. This project will lead to potential new treatments for dementia, improving the quality of life of many people and their families affected by dementia.