Leukotrienes (LTs) contribute to the neuropathology of chronic neurodegenerative disorders including Alzheimer’s Disease (AD), where they mediate neuroinflammation and neuronal cell-death. In consequence, blocking the action of Leukotrienes (LTs) ameliorates pathologies and improves cognitive function in animal models of neurodegeneration. Surprisingly, the source of Leukotrienes (LTs) in the brain is largely unknown. Here, we identified the Leukotriene (LT) synthesis rate-limiting enzyme 5-Lipoxygenase (5-Lox) primarily in neurons and to a lesser extent in a subpopulation of microglia in human Alzheimer´s Disease (AD) hippocampus brain sections and in brains of APP Swedish PS1 dE9 (APP-PS1) mice, a transgenic model for Alzheimer´s Disease (AD) pathology. The 5-Lipoxygenase (5-Lox) activating protein (FLAP), which anchors 5-Lipoxygenase (5-Lox) to the membrane and mediates the contact to the substrate arachidonic acid, was confined exclusively to microglia with the entire microglia population expressing 5-Lipoxygenase activating protein (FLAP). To define the contribution of microglia in the Leukotriene (LT) biosynthesis pathway, we ablated microglia using the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 in wildtype (WT) and APP-PS1 mice. Microglia ablation not only diminished the expression of FLAP and of the Leukotriene (LT) receptor Cysteinylleukotriene receptor 1 (CysLTR1), as expected based on their microglia cell type-specific expression, but also drastically reduced 5-Lipoxygenase (5-Lox) mRNA expression in the brain and its protein expression in neurons, in particular in wildtype (WT) mice. In conclusion i) microglia are key in Leukotriene (LT) biosynthesis, and ii) they regulate neuronal 5-Lipoxygenase (5-Lox) expression implying a yet unknown signaling mechanism between neurons and microglia.

中文翻译：

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小胶质细胞的消耗减少了阿尔茨海默氏病小鼠大脑中白三烯途径的关键元素。

白三烯（LTs）有助于慢性神经退行性疾病的神经病理学，包括阿尔茨海默氏病（AD），它们介导神经炎症和神经元细胞死亡。因此，在神经退行性动物模型中，阻断白三烯（LTs）的作用可改善病理状况并改善认知功能。令人惊讶的是，大脑中白三烯（LTs）的来源很大程度上未知。在这里，我们确定了白三烯（LT）合成限速酶5-Lipoxygenase（5-Lox）主要存在于神经元中，而在人类阿尔茨海默氏病（AD）海马脑部和大脑中的小胶质细胞亚群中则较少APP瑞典PS1 dE9（APP-PS1）小鼠的模型，这是阿尔茨海默氏病（AD）病理学的转基因模型。5-Lipoxygenase（5-Lox）活化蛋白（FLAP），将5-脂氧合酶（5-Lox）锚定在膜上并介导与底物花生四烯酸的接触的这种作用仅限于小胶质细胞，整个小胶质细胞群体均表达5-脂氧合酶激活蛋白（FLAP）。若要定义小胶质细胞在白三烯（LT）生物合成途径中的作用，我们在野生型（WT）和APP-PS1小鼠中使用集落刺激因子1受体（CSF1R）抑制剂PLX5622消融了小胶质细胞。小胶质细胞消融不仅减少了FLAP和白三烯（LT）受体半胱氨酸白三烯受体1（CysLTR1）的表达，这是基于它们的小胶质细胞类型特异性表达所预期的，而且还大大降低了5-Lipoxygenase（5-Lox）mRNA的表达。在神经元中，特别是在野生型（WT）小鼠中，其在大脑中的表达及其蛋白表达。