The Leukotriene Receptor Antagonist Montelukast Attenuates Neuroinflammation and Affects Cognition in Transgenic 5xFAD Mice

Abstract

Alzheimer’s disease (AD) is the most common form of dementia. In particular, neuroinflammation, mediated by microglia cells but also through CD8+ T-cells, actively contributes to disease pathology. Leukotrienes are involved in neuroinflammation and in the pathological hallmarks of AD. In consequence, leukotriene signaling—more specifically, the leukotriene receptors—has been recognized as a potential drug target to ameliorate AD pathology. Here, we analyzed the effects of the leukotriene receptor antagonist montelukast (MTK) on hippocampal gene expression in 5xFAD mice, a commonly used transgenic AD mouse model. We identified glial activation and neuroinflammation as the main pathways modulated by MTK. The treatment increased the number of Tmem119+ microglia and downregulated genes related to AD-associated microglia and to lipid droplet-accumulating microglia, suggesting that the MTK treatment targets and modulates microglia phenotypes in the disease model compared to the vehicle. MTK treatment further reduced infiltration of CD8+T-cells into the brain parenchyma. Finally, MTK treatment resulted in improved cognitive functions. In summary, we provide a proof of concept for MTK to be a potential drug candidate for AD and provide novel modes of action via modulation of microglia and CD8+ T-cells. Of note, 5xFAD females showed a more severe pathology, and in consequence, MTK treatment had a more pronounced effect in the females compared to the males. The effects on neuroinflammation, i.e., microglia and CD8+ T-cells, as well as the effects on cognitive outcome, were dose-dependent, therefore arguing for the use of higher doses of MTK in AD clinical trials compared to the approved asthma dose.

Leukotriene receptor antagonist use and cognitive decline in normal cognition, mild cognitive impairment, and Alzheimer’s dementia

“…A previous cohort study found that the use of montelukast was associated with a lower risk of using a dementia medication and entering a nursing home [ 12 ], which may be consistent with our finding that LTRAs were associated with less cognitive decline and slower clinical progression in dementia, although the link would require further study. The results also suggest that the protective effects of LTRAs on cognition shown in some preclinical literature may be relevant in humans; for instance, montelukast improved cognition in a mouse model of AD [ 7 ] and in aged rats [ 6 ].…”

“…The results contrast a preclinical study, which showed that the administration of montelukast improved memory in aged rats [ 6 ]. A second study using the 5xFAD mouse model found that montelukast did not improve memory outcomes but improved learning outcomes [ 7 ], suggesting possible benefits of LTRAs on some cognitive domains. Although there may be interspecies differences, the present findings suggest that the preclinical findings may be relevant in humans and that the associations with LTRAs were larger for language and processing speed than for memory.…”

“…Given the different findings between AD dementia, cognitively normal or MCI groups, it might be speculated that the mechanisms underlying the benefits of LTRAs are more relevant later in the course of AD progression. In rodent models, administration of montelukast enhanced neurogenesis, increased blood-brain barrier (BBB) integrity, and reduced neuroinflammation [ 6 , 7 , 36 ], which may be of benefit in the context of accumulated AD pathology. Although montelukast may penetrate the BBB [ 37 ], it is unclear if it enters the brain at concentrations sufficient to have effects in the central nervous system in humans at the doses currently used in asthma treatment.…”

“…Our analyses could not account for adherence, frequency of usage, duration of usage, or dosage of medications since these data were not collected in the UDS. Higher doses of montelukast resulted in better learning performance in 5xFAD mice, suggesting that a dose-response relationship may exist [ 7 ]. Future studies should examine possible dose effects and compare short- vs. long-term LTRA use.…”

Cognitive Effects of Montelukast: A Pharmaco-EEG Study

“…Thereby, Montelukast improved learning and memory functions, accompanied by reduced neuroinflammation, a restored BBB integrity and enhanced neurogenesis [ 13 ]. In subsequent studies, these outcomes have further been successfully translated to an animal model of Dementia with Lewy Bodies and of Alzheimer’s disease (AD), where treatment with montelukast restored memory, reduced the alpha-synuclein load, and impaired neuroinflammation [ 14 , 15 ].…”