The sialylated glyconjugates (SGC) are found in abundance on the surface of brain cells, where they form a dense array of glycans mediating cell/cell and cell/protein recognition in numerous physiological and pathological processes. Metabolic genetic blocks in processing and catabolism of SGC result in development of severe storage disorders, dominated by CNS involvement including marked neuroinflammation and neurodegeneration, the pathophysiological mechanisms of which are still discussed. SGC patterns in the brain are cell and organelle-specific, dynamic and maintained by highly coordinated processes of their biosynthesis, trafficking, processing and catabolism. The changes in the composition of SGC during development and aging of the brain cannot be explained based solely on the regulation of the SGC-synthesizing enzymes, sialyltransferases, suggesting that neuraminidases (sialidases) hydrolysing the removal of terminal sialic acid residues also play an essential role. In the current review we summarize the roles of three mammalian neuraminidases: neuraminidase 1, neuraminidase 3 and neuraminidase 4 in processing brain SGC. Emerging data demonstrate that these enzymes with different, yet overlapping expression patterns, intracellular localization and substrate specificity play essential roles in the physiology of the CNS.