The Leukotriene Receptor Antagonist Montelukast Attenuates Neuroinflammation and Affects Cognition in Transgenic 5xFAD Mice
| Autor: | Michael, Johanna, Zirknitzer, Julia, Unger, Michael Stefan, Poupardin, Rodolphe, Rieß, Tanja, Paiement, Nadine, Zerbe, Horst, Hutter-Paier, Birgit, Reitsamer, Herbert, Aigner, Ludwig |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cyclopropanes
Inflammation cognition microglia Brain Mice Transgenic Acetates CD8-Positive T-Lymphocytes Sulfides RNAseq leukotriene receptor antagonist 5xFAD Article lcsh:Chemistry Mice lcsh:Biology (General) lcsh:QD1-999 Alzheimer Disease montelukast Quinolines Animals Leukotriene Antagonists Alzheimer’s disease lcsh:QH301-705.5 cysteinyl leukotrienes |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 2782, p 2782 (2021) International Journal of Molecular Sciences Volume 22 Issue 5 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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