Final Activity Report Summary - BRAIN TOLLS (Innate signals for brain homeostasis) The proposed research aimed to identify novel ligands that trigger microglial responses to brain injury. Microglia are cells that become activated in the injured or inflamed brain. A class of cell-signalling receptors called Toll-like receptors (TLRs) are suggested to recognise molecular entities generated in response to neuronal injury and to signal microglial response. This project examined expression of TLRs by microglia and identified molecules, released by neurons that triggered microglia via TLRs. In vivo data had shown selective and specific upregulation of TLR's by microglia in response to synaptic degeneration. Tissue culture systems were established to allow analysis of microglial responses to defined stimuli. Molecular affinity, antibody, and synthetic and pharmacologic agents were used in conjunction with genetically-modified microglia to define involvement of TLRs and to characterise potential agonist ligands. Results show that treatment of neurons with adenosine, a neuromodulator associated with injury responses, induced production of a novel lipoprotein moiety that acted through a TLR on microglia to signal for production of a cytokine (tumour necrosis factor-alpha) response.