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

International Journal of Molecular Sciences

Johanna Michael¹  Julia Zirknitzer¹  MichaelStefan Unger¹  Tanja Rieß¹  Ludwig Aigner¹  Horst Zerbe²  Nadine Paiement²  Birgit Hutter-Paier³  Herbert Reitsamer⁴  Rodolphe Poupardin⁵ 

[1] Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria;IntelgenX Corp., Saint-Laurent, QC H4S 1Y2, Canada;QPS Neuropharmacology, 8074 Grambach/Graz, Austria;Research Program for Experimental Ophthalmology, Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria;Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria;

关键词: leukotriene receptor antagonist;    cysteinyl leukotrienes;    montelukast;    5xFAD;    cognition;    Alzheimer’s disease;   

DOI  :  10.3390/ijms22052782

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown