The elusive pathways behind montelukast's repurposing for Alzheimer's disease

Background and purpose: Montelukast, an antagonist of the cysteinyl leukotrienes receptor 1, has been proposed for repurposing for the treatment of neurodegenerative disorders, including Alzheimer’s disease. Clinical trials are ongoing but the mechanisms supporting this repurposing are still poorly understood. Experimental Approach: Taking advantage of proteomics datasets deposited in public repositories, data from mouse brain and a neuronal chicken model exposed to the drug were reinterpreted in view of the repurposing proposal. Key Results: Montelukast increases the levels of presenilin 1, nicastrin, neprilysin, and insulin-degrading enzyme, all of which are involved in the amyloid aggregation and clearance processes. Hexokinase 1, malate and isocitrate dehydrogenate enzymes, from central metabolism pathways, are also affected. Conclusions and Implications: The data suggest that montelukast is a modulator of the amyloid clearance process, favouring the removal of aggregates and counterbalancing the overall amyloidogenic process. Montelukast also acts on energy supply pathways, compensating the ageing-associated decrease of the basal cell metabolism. Taken together, these actions of montelukast clearly support its repurposing as a candidate for Alzheimer’s disease management.