Department of Medical Biology, Université du Québec à Trois-Rivières, 3351 boul. des Forges, G9A 5H7, Trois-Rivières, QC, Canada.
Department of Biomedical Sciences, Section of Neurosciences, University of Cagliari, Cagliari, Italy.
Mol Neurobiol. 2021 Jun;58(6):3000-3014. doi: 10.1007/s12035-021-02328-7. Epub 2021 Feb 18.
Neuroinflammation has been implicated in the pathogenesis of neurodegeneration and is now accepted as a common molecular feature underpinning neuronal damage and death. Palmitic acid (PA) may represent one of the links between diet and neuroinflammation. The aims of this study were to assess whether PA induced toxicity in neuronal cells by modulating microglial inflammatory responses and/or by directly targeting neurons. We also determined the potential of oleic acid (OA), a monounsaturated fatty acid, to counteract inflammation and promote neuroprotection. We measured the ability of PA to induce the secretion of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), the induction of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathways, as well as the phosphorylation of c-Jun, and the expression of inducible nitric oxide synthase (iNOS). Finally, to determine whether PA exerted an indirect neurotoxic effect on neuronal cells, we employed a microglia-neuron co-culture paradigm where microglial cells communicate with neuronal cells in a paracrine fashion. Herein, we demonstrate that PA induces the activation of the NF-κB signalling pathway and c-Jun phosphorylation in N9 microglia cells, in the absence of increased cytokine secretion. Moreover, our data illustrate that PA exerts an indirect as well as a direct neurotoxic role on neuronal PC12 cells and these effects are partially prevented by OA. These results are important to establish that PA interferes with neuronal homeostasis and suggest that dietary PA, when consumed in excess, may induce neuroinflammation and possibly concurs in the development of neurodegeneration.
神经炎症与神经退行性变的发病机制有关，现在被认为是神经元损伤和死亡的共同分子特征。棕榈酸（PA）可能代表饮食与神经炎症之间的联系之一。本研究旨在评估 PA 是否通过调节小胶质细胞炎症反应和/或直接靶向神经元来诱导神经元细胞毒性。我们还确定了单不饱和脂肪酸油酸（OA）抵消炎症和促进神经保护的潜力。我们测量了 PA 诱导白细胞介素 6（IL-6）和肿瘤坏死因子-α（TNF-α）分泌、核因子 kappa 轻链增强子活化 B 细胞（NF-κB）信号通路诱导、c-Jun 磷酸化以及诱导型一氧化氮合酶（iNOS）表达的能力。最后，为了确定 PA 是否对神经元细胞产生间接神经毒性作用，我们采用小胶质细胞-神经元共培养模型，其中小胶质细胞以旁分泌方式与神经元细胞通讯。在此，我们证明 PA 在没有增加细胞因子分泌的情况下诱导 N9 小胶质细胞中 NF-κB 信号通路和 c-Jun 磷酸化的激活。此外，我们的数据表明 PA 对神经元 PC12 细胞具有间接和直接的神经毒性作用，而 OA 部分阻止了这些作用。这些结果对于确定 PA 干扰神经元内稳态很重要，并表明饮食中的 PA 如果过量摄入，可能会引发神经炎症，并可能有助于神经退行性变的发展。
