Microglial interactions with neurons in health, ageing and neurodegeneration

Microglia are brain macrophages involved in shaping, protecting and killing brain neurons in development, health, aging and neurodegeneration. Brain inflammation and microglial activation occurs with over-nutrition, aging and neuroinflammation. 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, which we have called 'phagoptosis'. Phagoptosis is cell death by phagocytosis of the cell, and thus is prevented by blocking phagocytosis. Phagocytosis of an otherwise-viable cell may occur because the cell is stressed, activated, senescent, damaged, recognised as non-self or misrecognised. And phagoptosis is greatly enhanced during inflammation. This project will be investigating the signals and receptors involved in this process, and whether phagocytosis is beneficial or detrimental in over-nutrition and aging. In particular, we will model over-nutrition and aging in brain cell cultures and hippocampal slice cultures; and test the roles of the phagocytic receptors VNR, MerTK or P2Y6 receptors in neuronal and synaptic loss. We will be testing the hypothesis that blocking these phagocytic receptors prevents neuronal and synaptic loss in over-nutrition and aging, 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.