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

International Journal of Molecular Sciences, 2021 · DOI: 10.3390/ijms22052782 · Published: March 9, 2021

Simple Explanation

Alzheimer's disease (AD) is characterized by neuroinflammation, where immune cells like microglia and T-cells contribute to the disease. Leukotrienes, substances involved in inflammation, play a role in AD pathology. Blocking leukotriene receptors is a potential treatment strategy. This study tested montelukast (MTK), a drug that blocks leukotriene receptors, on 5xFAD mice, a model for AD. The study looked at how MTK affected genes in the brain and whether it could improve cognitive function. The findings suggest that MTK can modify the activity of microglia and reduce the infiltration of T-cells into the brain, ultimately improving cognitive functions in these mice. The effects were more noticeable in female mice, which tend to show a more severe form of the disease in this model.

Study Duration

13 weeks

Participants

45 transgenic 5xFAD mice

Evidence Level

Not specified

Key Findings

1
MTK treatment modulated glial activation and neuroinflammation pathways in 5xFAD mice. The treatment increased Tmem119+ microglia and downregulated genes related to AD-associated microglia.
2
MTK treatment further reduced infiltration of CD8+T-cells into the brain parenchyma, suggesting a reduction in the adaptive immune response within the brain.
3
MTK treatment resulted in improved cognitive functions in the 5xFAD mice, demonstrating a potential therapeutic benefit.

Research Summary

This study investigates the effects of montelukast (MTK), a leukotriene receptor antagonist, on neuroinflammation and cognition in 5xFAD mice, a model for Alzheimer's disease (AD). The results showed that MTK treatment modulated microglia and reduced CD8+ T-cell infiltration into the brain parenchyma, suggesting a novel mode of action for MTK in AD. The study provides a proof of concept for MTK as a potential drug candidate for AD, with dose-dependent effects on neuroinflammation and cognitive outcome, suggesting the use of higher doses in clinical trials.

Practical Implications

Potential AD Therapy

Montelukast, an existing drug, could be repurposed as a treatment for Alzheimer's disease.

Targeting Neuroinflammation

Modulating microglia and T-cell infiltration may be key to treating AD.

Dosage Considerations

Higher doses of montelukast than those used for asthma may be necessary for cognitive benefits in AD.

Study Limitations

1
This study did not aim to include WT vehicle- or WT MTK-treated animals
2
The effect of MTK on cognition might be more pronounced in older animals
3
The long handling period prior to the test might have led to a lower motivation to escape from the platform during the Barnes maze test

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