Neuroinflammation in frontotemporal dementia: The role of microglia in TDP-43-related disease
The brains of patients with frontotemporal dementia (FTD) show inflammation in affected regions, where neurodegeneration has occurred. In the brain, immune cells known as microglia are the main cell type that controls this inflammatory response. Microglia provide a protective surveillance function in the brain to allow rapid response to injury or disease but they can also take on toxic properties that drive neuron death. In FTD, it remains unclear whether inflammatory microglia are protective or toxic to neurons. In this study, microglia and inflammatory molecules will be analysed over time in recently-developed genetically-modified mice that develop disease similar to human FTD, and these mice will be treated with an experimental drug to prevent brain inflammation. Findings from this project will therefore determine if pharmacological alteration of the microglial inflammatory response could be used to modify disease development and progression in FTD.
Frontotemporal dementia (FTD) is a devastating and incurable neurodegenerative disease caused by the dysfunction and loss of neurons in the brain. Approximately half of all cases of FTD are pathologically defined by the presence of TAR DNA-binding protein 43 (TDP-43) inclusions in degenerating neurons. However, the processes that drive or modulate neurodegeneration in FTD remain poorly defined. From human autopsy studies it is known that neuroinflammation, mediated primarily by microglia in the brain, is a feature of FTD. However it is unclear which inflammatory molecules are produced by microglia in FTD, whether the neuroinflammatory response occurs early in disease, and how this process changes over time in the brain. In order to define whether activated microglia are protective or toxic to neurons in FTD, this project will comprehensively analyse microglial activation in newly generated transgenic mice which develop brain TDP-43 pathology reminiscent of human disease. Using neurons and microglia in tissue culture, and an inhibitor of microglial activation in vivo, this project will also identify how neurodegeneration is affected by microglia in TDP-43-related FTD. These studies will therefore guide development of therapeutic strategies aimed at modulation of microglial activation in FTD.
Dr Walker is an NHMRC CJ Martin Biomedical Research Fellow at the Department of Biomedical Sciences, Macquarie University.