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.

Aging is associated with loss of cognitive functions and with an increased risk for neurodegenerative diseases such as dementias. Chronic inflammatory reactions in the brain, i.e. neuroinflammation, are increasingly recognized to be responsible for brain aging as well as for dementias. The Hertha-Firnberg fellowship gave me the possibility to discover and to explore central mechanisms of neuroinflammation, and moreover, to modulate these mechanisms demonstrating the therapeutic potential of such strategies. I demonstrated that leukotrienes, small lipid-like signaling molecules, which are well-known from inflammatory reactions such as in asthma, play an essential role in brain aging and dementia. The pharmacological inhibition of the leukotriene signaling led to a rejuvenation of the brains of aged and of demented animals. It lowered the brain inflammation, induced regeneration, and led to a restoration of learning and memory. These findings triggered a drug development program with the product being currently already tested in patients with dementia. The Hertha-Firnberg fellowship allowed me to go abroad and to work at Stanford University, California, in the lab of Tony Wyss-Coray, one of the worlds leading experts in brain aging and rejuvenation. I discovered a new mechanism of brain aging and deciphered it at the molecular and cellular level. The mechanism is centered around small lipid droplets, which appear along brain aging in the brains inflammatory cells, the so-called microglia, which are in charge of waste-disposal in the brain. The lipid droplets are related to massive loss of waste-disposal function in these cells and to increased neuroinflammation. Vice versa, inhibiting the formation of these lipid droplets leads to functional improvements of these cells, and thus might resemble a novel therapeutic approach for the treatment of neurodegenerative disease such as dementia.