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Abstract：
BACKGROUND: Brain inflammation contributes significantly to the pathophysiology of Alzheimer\'s disease, and it is manifested by glial cell activation, increased production of cytokines/chemokines, and a shift in lipid mediators from a pro-homeostatic to a pro-inflammatory profile. However, whether the production of bioactive lipid mediators is affected at earlier stages, prior to the deposition of Aβ plaques and tau hyperphosphorylation, is unknown. The differential contribution of an evolving amyloid and tau pathology on the composition and abundance of membrane phospholipids and bioactive lipid mediators also remains unresolved.
METHODS: In this study, we examined the cortical levels of DHA- and AA-derived bioactive lipid mediators and of membrane phospholipids by liquid chromatography with tandem mass spectrometry in transgenic rat models of the Alzheimer\'s-like amyloid and tau pathologies at early and advanced pathological stages.
RESULTS: Our findings revealed a complex balance between pro-inflammatory and pro-resolving processes in which tau pathology has a more pronounced effect compared to amyloid pathology. At stages preceding tau misfolding and aggregation, there was an increase in pro-resolving lipid mediators (RVD6 and NPD1), DHA-containing phospholipids and IFN-γ levels. However, in advanced tau pathology displaying NFT-like inclusions, neuronal death, glial activation and cognitive deficits, there was an increase in cytokine and PGD2, PGE2, and PGF2α generation accompanied by a drop in IFN-γ levels. This pathology also resulted in a marked increase in AA-containing phospholipids. In comparison, pre-plaque amyloid pathology already presented high levels of cytokines and AA-containing phospholipids together with elevated RVD6 and NPD1 levels. Finally, Aβ plaque deposition was accompanied by a modest increase in prostaglandins, increased AA-containing phospholipids and reduced DHA-containing phospholipids.
CONCLUSIONS: Our findings suggest a dynamic trajectory of inflammatory and lipid mediators in the evolving amyloid and tau pathologies and support their differing roles on membrane properties and, consequentially, on signal transduction.
METHODS: In this study, we examined the cortical levels of DHA- and AA-derived bioactive lipid mediators and of membrane phospholipids by liquid chromatography with tandem mass spectrometry in transgenic rat models of the Alzheimer\'s-like amyloid and tau pathologies at early and advanced pathological stages.
RESULTS: Our findings revealed a complex balance between pro-inflammatory and pro-resolving processes in which tau pathology has a more pronounced effect compared to amyloid pathology. At stages preceding tau misfolding and aggregation, there was an increase in pro-resolving lipid mediators (RVD6 and NPD1), DHA-containing phospholipids and IFN-γ levels. However, in advanced tau pathology displaying NFT-like inclusions, neuronal death, glial activation and cognitive deficits, there was an increase in cytokine and PGD2, PGE2, and PGF2α generation accompanied by a drop in IFN-γ levels. This pathology also resulted in a marked increase in AA-containing phospholipids. In comparison, pre-plaque amyloid pathology already presented high levels of cytokines and AA-containing phospholipids together with elevated RVD6 and NPD1 levels. Finally, Aβ plaque deposition was accompanied by a modest increase in prostaglandins, increased AA-containing phospholipids and reduced DHA-containing phospholipids.
CONCLUSIONS: Our findings suggest a dynamic trajectory of inflammatory and lipid mediators in the evolving amyloid and tau pathologies and support their differing roles on membrane properties and, consequentially, on signal transduction.
摘要：
背景：脑部炎症对阿尔茨海默病的病理生理学有重要贡献，它表现为神经胶质细胞活化，增加细胞因子/趋化因子的产生，以及脂质介质从促进稳态到促炎的转变。然而,生物活性脂质介质的产生是否在早期阶段受到影响，在Aβ斑块沉积和tau过度磷酸化之前，是未知的。不断发展的淀粉样蛋白和tau病理对膜磷脂和生物活性脂质介质的组成和丰度的不同贡献也仍未解决。
方法：在本研究中，我们在早期和晚期病理阶段的阿尔茨海默样淀粉样蛋白和tau病理的转基因大鼠模型中,通过液相色谱-串联质谱法检测了DHA和AA衍生的生物活性脂质介质和膜磷脂的皮质水平.
结果：我们的发现揭示了促炎和促解过程之间的复杂平衡，其中tau病理学与淀粉样蛋白病理学相比具有更明显的作用。在tau错误折叠和聚集之前的阶段，促分辨脂质介质（RVD6和NPD1）增加，含DHA的磷脂和IFN-γ水平。然而,在显示NFT样包涵体的高级tau病理学中，神经元死亡，神经胶质激活和认知缺陷，细胞因子和PGD2，PGE2和PGF2α的产生增加，同时IFN-γ水平下降。这种病理学还导致含AA的磷脂的显著增加。相比之下,斑块前淀粉样蛋白病理已经呈现高水平的细胞因子和含AA的磷脂以及升高的RVD6和NPD1水平.最后,Aβ斑块沉积伴随着前列腺素的适度增加，增加含AA的磷脂和减少含DHA的磷脂。
结论：我们的研究结果表明，在不断发展的淀粉样蛋白和tau病理中，炎症和脂质介质的动态轨迹，并支持它们在膜特性上的不同作用，因此，关于信号转导。
方法：在本研究中，我们在早期和晚期病理阶段的阿尔茨海默样淀粉样蛋白和tau病理的转基因大鼠模型中,通过液相色谱-串联质谱法检测了DHA和AA衍生的生物活性脂质介质和膜磷脂的皮质水平.
结果：我们的发现揭示了促炎和促解过程之间的复杂平衡，其中tau病理学与淀粉样蛋白病理学相比具有更明显的作用。在tau错误折叠和聚集之前的阶段，促分辨脂质介质（RVD6和NPD1）增加，含DHA的磷脂和IFN-γ水平。然而,在显示NFT样包涵体的高级tau病理学中，神经元死亡，神经胶质激活和认知缺陷，细胞因子和PGD2，PGE2和PGF2α的产生增加，同时IFN-γ水平下降。这种病理学还导致含AA的磷脂的显著增加。相比之下,斑块前淀粉样蛋白病理已经呈现高水平的细胞因子和含AA的磷脂以及升高的RVD6和NPD1水平.最后,Aβ斑块沉积伴随着前列腺素的适度增加，增加含AA的磷脂和减少含DHA的磷脂。
结论：我们的研究结果表明，在不断发展的淀粉样蛋白和tau病理中，炎症和脂质介质的动态轨迹，并支持它们在膜特性上的不同作用，因此，关于信号转导。
