Supervisor View Full Details

• neuroscience and mental health

• Medicine

• Dementia
• Immunology
• Neurophysiology
• Neuropsychiatry
• Psychiatry

My research group focuses on assessing the impact of microglial activation on the neuroinflammation and loss of neuronal function that develops with age and in Alzheimer's disease (AD). Microglia play an important role in maintaining homeostasis in the brain under normal conditions but, in the aged brain, and especially in neurodegenerative conditions, they respond more to inflammatory stimuli, including amyloid-?, the peptide that predominates in the plaques associated with AD. As a result, they shift to an M1-like phenotype with glycolysis as their energy source. The developing age-related neuroinflammation, which is coupled with evidence of inflammasome activation in microglia and reduced neuronal function, increases amyloid pathology in a mouse model of AD. Recent data from genome-wide association studies have indicated that inflammation is likely to be a significant factor in driving the pathology that accompanies AD and therefore we are investigating significant questions like (a) is microglial activation the key inducer of neuroinflammation and consequently of loss of neuronal function? (b) what is responsible for stimulating microglial activation? (c) why does age/AD prevent microglia from switching back to their protective state? (d) what strategies can be used to modulate microglial activation so that their plasticity can be restored and the deteriorating neuronal function and pathology be limited or prevented?

The momentum behind investigating a role for neuroinflammation in Alzheimer's disease (AD) increased significantly when data from GWAS identified polymorphisms in several genes known to play a role in inflammation and immune modulation as risk factors in AD. The link between the immune system/peripheral inflammatory changes and cognition in AD is consolidated by the finding that cognitive decline was accelerated in patients who experienced acute systemic inflammation.

The main role of microglia, the primary immune cells in the brain, is protective; the cells rapidly respond to stimuli that are perceived as a threat to homeostasis but persistent microglial activation, with the accompanying excessive release of inflammatory molecules, causes neuronal damage. Our evidence indicates that inflammasome activation contributes to this persistent neuroinflammation.

The aims of this project are to identify the factors that are responsible for triggering inflammasome assembly in aged mice and, particularly, in a mouse model of AD and to evaluate the impact of novel small molecule inhibitors of the inflammasome.

Evidence form this laboratory has linked inflammasome assembly with a change in the metabolic profile of microglia and therefore the project will also evaluate the possibility that chronic microglial activation can be modulated by factors that impact on metabolic function.