Brain Rejuvenation through Inhibition of Leukotriene Signaling

With age, brain homeostasis changes and cognitive skills decline, and the risk to develop dementia or neurodegenerative diseases increases dramatically. It is thus essential to understand the age-related brain changes responsible for cognitive declines (i.e, amongst others, a dramatic reduction in neurogenesis, a high load of neuroinflammation, and decreased synaptic density). Targeting such mechanisms might rejuvenate the aged brain with the aim to restore cognitive functions in the elderly. There is increasing amount of evidence that the lipid pro-inflammatory leukotrienes are involved in age-related brain changes, which turns these substances into highly promising targets for brain rejuvenation. Current knowledge, however, on the exact role of leukotrienes in structural and functional processes of brain aging is limited. We recently demonstrated that montelukast, a leukotriene receptor antagonist, restores several structural brain changes and, most intriguingly, improves learning and memory in aged rats. The mode of action of Montelukast within the brain, however, and the role of the leukotriene receptor GPR17, the most abundant leukotriene receptor in neural progenitors, in brain aging and in the brain rejuvenation are so far unknown. Thus, the present proposal focuses on the role of leukotrienes in brain aging, and on the molecular and cellular mechanisms underlying the rejuvenating effects of the leukotriene receptor antagonist Montelukast in the aged brain. We will (i) study the involvement of leukotrienes in structural and functional brain aging by increasing CNS leukotriene levels in young rats. Using GPR17 knockout and GPR17 siRNA knockdown mice, we will (ii) analyse the impact of the leukotriene receptor GPR17 on neurogenesis and neuroinflammation in vitro, and the relevance of GPR17 on brain aging and on the brain rejuvenating effects of Montelukast in vivo. In a long term-perspective, we are intended to (i) contribute to the general understanding of brain aging and brain rejuvenation, and, by decoding the molecular and cellular mechanisms underlying the rejuvenating effects of montelukast, we (ii) aim to translate the concept of brain rejuvenation by targeting leukotriene signaling into the clinics as a promising approach to reverse cognitive decline during aging and in neurodegenerative diseases.

No additional funding sources recorded.