Microglia in neurodegeneration
Microglia are brain macrophages involved in shaping, protecting and killing brain neurons in development, aging and neurodegeneration. We have been investigating the mechanisms by which microglia become inflamed and damage neurons. Recently, we have found that inflamed microglia can phagocytose (i.e. eat) live neurons, and thereby cause neuronal death and loss. And there is now compelling evidence that excess microglial phagocytosis of synapses contributes to Alzheimer’s disease, schizophrenia and other brain diseases. This is exciting because in principle blocking the right microglial receptor could protect in these and other diseases where synopsis and neurons are lost due to excessive microglial phagocytosis.
This project will be investigating the signals and receptors involved in this process, and whether phagocytosis is beneficial or detrimental in particular pathologies. In particular, we will test the roles of the phagocytic receptors MerTK, P2Y6 and P2Y12 receptors in neuronal and synaptic loss. We will be testing the hypothesis that blocking these phagocytic receptors prevents neuronal and synaptic loss in models of neurodegeneration, and consequently might be used as therapeutic targets. The project will use cell culture, fluorescence microscopy, immunohistochemistry, Western blotting, molecular cell biology and animal models where appropriate.
Vilalta A, Brown GC (2017) Neurophagy - the phagocytosis of live neurons and synapses by glia - contributes to brain development and disease. FEBS J. Nov 10.
Nomura K, Vilalta A, Allendorf DH, Hornik TC, Brown GC (2017) Activated Microglia Desialylate and Phagocytose Cells via Neuraminidase, Galectin-3, and Mer Tyrosine Kinase. J Immunol 198, 4792-4801.
Brown GC, St George-Hyslop PH (2017) Deciphering microglial diversity in Alzheimer's disease. Science 356, 1123-1124.
Yip PK et al (2017) Galectin-3 released in response to traumatic brain injury acts as an alarmin orchestrating brain immune response and promoting neurodegeneration. Sci Rep 7, 41689.
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FTE Category A staff submitted: 189.63
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