Prolyl oligopeptidase (POP) is a cytosolic serine protease with prominent expression in the brain. Inhibition of this enzyme leads to cognition-enhancing and neuroprotective effects in animal models with cognitive deficits. However, the biological function of POP remains unknown. Although in the past it was though that its catalytic activity was responsible for its physiological role, lately it has been hypothesized that POP is involved in the inositol pathway and that it interacts with several proteins, including α-tubulin, thereby implying that its function may be related to protein-protein interactions. In this review, we analyze the destabilization of microtubules in neurological diseases such as schizophrenia, Parkinson's, Alzheimer's and Huntington's disease. Given the interaction of POP with α-tubulin, we discuss the relevance of this protease in the modulation of synaptic processes. In this context, we also examine the potential of POP as a promising target for the treatment of cognitive impairment.