Microglia depletion diminishes key elements of the leukotriene pathway in the brain of Alzheimer’s Disease mice

Acta Neuropathologica Communications, 2020 · DOI: https://doi.org/10.1186/s40478-020-00989-4 · Published: January 1, 2020

Immunology Neurology

Simple Explanation

Leukotrienes (LTs) are linked to brain issues in diseases like Alzheimer's, causing inflammation and nerve cell death. Blocking LTs can help in animal models. The study found that a key enzyme for making LTs, 5-Lipoxygenase (5-Lox), is mostly in brain cells called neurons and, to some extent, in microglia in Alzheimer's brains. When microglia were removed in mice, it not only reduced things normally found in microglia but also unexpectedly lowered the amount of 5-Lox in the brain and neurons, especially in normal mice.

Study Duration

4 weeks

Participants

Female and male APP Swedish PS1 dE9 mice and wildtype mice

Evidence Level

Not specified

Key Findings

1
FLAP, a key activator of the LT pathway, is found in all microglia and no other brain cells.
2
5-Lox, an enzyme involved in LT production, is mainly in neurons, with some presence in microglia, especially in Alzheimer's conditions.
3
Removing microglia decreased LT pathway components like FLAP and Cysltr1, and surprisingly reduced neuronal 5-Lox expression, mainly in normal mice.

Research Summary

The study investigates the role of microglia in leukotriene (LT) biosynthesis in the context of Alzheimer's Disease (AD). It identifies the key enzyme 5-Lipoxygenase (5-Lox) primarily in neurons and to a lesser extent in microglia. Microglia ablation experiments using a CSF1R inhibitor (PLX5622) revealed that microglia are key in LT biosynthesis and regulate neuronal 5-Lipoxygenase (5-Lox) expression. The findings suggest a signaling mechanism between neurons and microglia in the context of neuroinflammation, with potential implications for the use of anti-LT drugs in CNS diseases.

Practical Implications

Therapeutic Target Identification

The leukotriene signaling pathway, particularly the role of microglia and neuronal interactions, presents a druggable target for Alzheimer's disease.

Microglia as a Therapeutic Target

Modulating microglia activity to reduce neuroinflammation and regulate leukotriene synthesis could be a potential therapeutic strategy.

Repurposing Anti-LT Drugs

Existing anti-LT drugs might be beneficial for treating diseases of the central nervous system (CNS), including Alzheimer's disease, by targeting the identified cellular components involved in LT synthesis.

Study Limitations

1
The explicit function or functions of 5-Lox in neurons are still elusive and need further investigations.
2
The clear identity of the microglia subpopulation requires further investigation.
3
Single cell transcriptome profiling of neurodegenerative brains will certainly be required to further underscore our findings.

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