Differential effect of an evolving amyloid and tau pathology on brain phospholipids and bioactive lipid mediators in rat models of Alzheimer-like pathology.
Sonia Do Carmo, Marie-Audrey I Kautzmann, Surjyadipta Bhattacharjee, Bokkyoo Jun, Carolyn Steinberg, Joshua T Emmerson, Janice C Malcolm, Quentin Bonomo, Nicolas G Bazan, A Claudio Cuello
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引用次数: 0
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.
背景:脑部炎症在阿尔茨海默病的病理生理学中起着重要作用,表现为神经胶质细胞活化、细胞因子/趋化因子分泌增加,以及脂质介质从有利于稳态转变为有利于炎症。然而,在 Aβ 斑块沉积和 tau 过度磷酸化之前的早期阶段,生物活性脂质介质的产生是否会受到影响尚不清楚。淀粉样蛋白和tau病理学的演变对膜磷脂和生物活性脂质介质的组成和丰度的不同影响也仍未解决:在这项研究中,我们通过液相色谱-串联质谱法检测了阿尔茨海默氏症类淀粉样蛋白和tau病理早期和晚期转基因大鼠皮质中DHA和AA衍生的生物活性脂质介质以及膜磷脂的水平:结果:我们的研究结果表明,在促炎症过程和促溶解过程之间存在着复杂的平衡,其中tau病理学的影响比淀粉样病理学更为明显。在 tau 蛋白错误折叠和聚集之前的阶段,促溶解脂质介质(RVD6 和 NPD1)、含 DHA 的磷脂和 IFN-γ 水平均有所增加。然而,在显示 NFT 样包涵体、神经元死亡、神经胶质细胞活化和认知障碍的晚期 tau 病理学中,细胞因子和 PGD2、PGE2 和 PGF2α 生成增加,而 IFN-γ 水平下降。这种病理变化还导致含 AA 的磷脂明显增加。相比之下,斑块淀粉样病变前的细胞因子和含 AA 磷脂水平已经很高,RVD6 和 NPD1 水平也有所升高。最后,Aβ斑块沉积伴随着前列腺素的适度增加、含AA磷脂的增加和含DHA磷脂的减少:我们的研究结果表明,炎症介质和脂质介质在淀粉样蛋白和 tau 病理学的演变过程中呈现出动态轨迹,并支持它们对膜特性以及信号转导所起的不同作用。
期刊介绍:
The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes.
Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems.
The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.