Leukotriene A4 hydrolase inhibition improves age-related cognitive decline via modulation of synaptic function

Abstract

Leukotrienes, a class of inflammatory bioactive lipids, are well studied in the periphery, but less is known of their importance in the brain. We identified that the enzyme leukotriene A4 hydrolase (LTA4H) is expressed in healthy mouse neurons, and inhibition of LTA4H in aged mice improves hippocampal dependent memory. Single-cell nuclear RNA sequencing of hippocampal neurons after inhibition reveals major changes to genes important for synaptic organization, structure, and activity. We propose that LTA4H inhibition may act to improve cognition by directly inhibiting the enzymatic activity in neurons, leading to improved synaptic function. In addition, LTA4H plasma levels are increased in both aging and Alzheimer’s disease and correlated with cognitive impairment. These results identify a role for LTA4H in the brain, and we propose that LTA4H inhibition may be a promising therapeutic strategy to treat cognitive decline in aging related diseases.