Microglia are the innate immune cells of the central nervous system (CNS) and play key roles in mediating the removal of dead or dying neurons, neurotoxic aggregates or neuronal debris, thus contributing to CNS health. Research in the recent years however has linked microglial activity to neurodegenerative processes brought about by excessive phagocyto- sis of viable neurons or synapses and the release of proinflammatory cytokines. Microglia require certain on or off signals that induce or reduce their activity. Understanding how microglia regulate these signals is key to finding novel ways of modulating microglial ac- tivation. A recently discovered mechanism of immune cell regulation outside the CNS is desialylation which is the removal of cell surface sialic acid residues by enzymes called sial- idases or neuraminidases. Sialic acids are 9-carbon, negatively charged monosaccharides that normally form the terminal residue of the mammalian cells’ glycocalyx. A murine microglial cell line and primary microglia were used to study if desialylation may occur in the brain’s innate immune cells. The experiments in this dissertation demonstrate that under inflammatory conditions microglia remove their terminal sialic acid sugars by a neuraminidase enzyme that is exposed on the cell surface after microglial activation by lipopolysaccharide (LPS) or Alzheimer’s Disease associated proteins Amyloid-beta (Abeta ) and tau. Neuraminidase enzyme Neu1 was found on the cell surface of LPS-activated microglia using surface biotinylation and antibody binding experiments. Moreover, knock down of Neu1 reduced the microglial surface sialidase activity induced by LPS, indicating that this enzyme may be responsible for surface desialylation of microglial cells. LPS- stimulation also encouraged release of a neuraminidase into the culture supernatants of microglia, which was reduced by Neu1 knockdown. The functional consequences of microglial desialylation in cis were then investigated by adding an exo-sialidase from bacterial origin. Sialidase treatment of microglia stimulated phagocytosis and induced cytokine release. Toll-like receptor 4 (TLR4) inhibition or knockdown suppressed sialidase-induced cytokine release indicating that sialidase triggers TLR4 activation. Moreover, knockdown of the endogenous Neu1 enzyme reduced cytokine release. Neu1 and TLR4 were found to be in proximity to each other on the surface of LPS-stimulated microglia where Neu1 may also directly remove the sialic acids from TLR4 receptor. Thus surface Neu1 may increase the TLR4-mediated inflammatory response, potentially by desialylation of TLR4 and disruption of Siglec-E:TLR4 binding. As for the phagocytic response, sialidase treatment of microglial cells increased phagocytosis in vitro. Knockdown or inhibition of CD11b, a component of the pro-phagocytic receptor complement receptor 3 (CR3), effectively blocked this sialidase-induced upregulation of phagocytosis. Moreover, inflammation-induced loss in neuron-like nuclei was ameliorated by inhibition of sialidase by a small molecule, indicating that blockage of sialidase may be a novel druggable target for neurodegenerative disease research. The effect of microglia- induced desialylation in trans was also investigated by desialylating neurons by sialidase or conditioned medium from LPS-treated microglial cultures, and it was found that removal of sialic acids sensitised neurons to glutamate-induced cell death. Overall, this study suggests that inhibition of surface or secreted neuraminidase may have beneficial effects in contexts of chronic neuroinflammation and microglia-mediated neurodegeneration.