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.
Highlights
The inflammatory processes are shaped by innate immunity in the form of highly dynamic microglia cells that are responsible for the release of pro- and antiinflammatory substances, as well as for phagocytosis of cellular debris, a process which is increasingly disrupted during the course of Alzheimer’s disease (AD) [6,7]
The present study aimed to illustrate the effects of prolonged MTK treatment on neuroinflammation and cognition in transgenic AD mice
5xFAD mice with a low (3.3 mg/kg/d) or high (10 mg/kg/d) dose of MTK or placebo for 13 weeks starting at 5 months of age, where these animals already have a pronounced
Summary
Other significantly downregulated biological processes were “leukocyte migration”, “positive regulation of cell migration”, “ROS metabolism” and “platelet activation” Genes annotated to these biological processes are presented in a heatmap summarized under the broad term of inflammation (Figure 2C). For the mouse model used in this study, sex differences in gene expression have been described, pointing towards a stronger impact of pathology in female mice [55,56] These findings had us analyze the set of DEGs in a sex-specific manner (Figure 2B). A separation of male (blue) and female (pink) animals can be seen in both the treatment and vehicle groups, where we observed that the untreated female mice exhibit higher row Z scores, supporting the hypothesis that female mice exhibit a more pronounced pathology than males of the same age with regard to the gene expression in this heatmap (Figure 2C).
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