Lipopolysaccharide-induced neuroinflammation leads to the accumulation of ubiquitinated proteins and increases susceptibility to neurodegeneration induced by proteasome inhibition in rat hippocampus.
Lipopolysaccharide-induced neuroinflammation leads to the accumulation of ubiquitinated proteins and increases susceptibility to neurodegeneration induced by proteasome inhibition in rat hippocampus.
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DOI：
10.1186/1742-2094-9-87
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发表时间：
2012-05-04
影响因子：
9.3
通讯作者：
Ruano D
中科院分区：
文献类型：
--
作者：
Pintado C;Gavilán MP;Gavilán E;García-Cuervo L;Gutiérrez A;Vitorica J;Castaño A;Ríos RM;Ruano D
神经炎症和蛋白质积累是正常衰老和与年龄相关的神经退行性疾病的特征性标志。然而，这些因素在神经退行性过程中的关系知之甚少。我们以前已经表明，蛋白酶体抑制老年大鼠比年轻大鼠产生更高的神经退行性变，这表明其他与年龄相关的事件可能参与神经退行性变。我们评估了脂多糖（LPS）诱导的神经炎症作为蛋白酶体抑制诱导的海马神经变性的潜在协同危险因素的作用。将1 μL生理盐水或LPS（5 mg/mL）注射到年轻雄性Wistar大鼠海马中，以评价LPS诱导的神经炎症对蛋白质稳态的影响。在年轻大鼠中分析LPS和蛋白酶体抑制的协同效应，首先接受1 μL LPS，24 h后接受1 μL（5 mg/mL）蛋白酶体抑制剂lactacystin。在注射后的不同时间处死动物，分离并处理大肠杆菌，用于通过实时聚合酶链反应进行基因表达分析;通过蛋白质印迹进行蛋白质表达分析;通过荧光光谱法进行蛋白酶体活性分析;通过共聚焦显微镜进行免疫荧光分析;以及通过Fluoro-Jade B染色进行变性测定。LPS注射引起海马神经元泛素化蛋白的积累，E2泛素结合酶UB 2L 6的表达增加，蛋白酶体活性降低，免疫蛋白酶体含量增加。然而，LPS注射不足以产生神经变性。当与单独注射LPS或lactacystin（LT）相比时，神经炎症和蛋白酶体抑制的组合导致泛素化蛋白的更高神经元积累、促凋亡标记物的主要表达和增加的神经变性。我们的研究结果确定神经炎症是一个危险因素，增加了对蛋白酶体抑制诱导的神经退行性变的易感性。这些结果强调了神经炎症的调节是神经元保护的一种机制，这可能与这两种因素同时存在的情况有关，例如衰老和神经退行性疾病。
Neuroinflammation and protein accumulation are characteristic hallmarks of both normal aging and age-related neurodegenerative diseases. However, the relationship between these factors in neurodegenerative processes is poorly understood. We have previously shown that proteasome inhibition produced higher neurodegeneration in aged than in young rats, suggesting that other additional age-related events could be involved in neurodegeneration. We evaluated the role of lipopolysaccharide (LPS)-induced neuroinflammation as a potential synergic risk factor for hippocampal neurodegeneration induced by proteasome inhibition. Young male Wistar rats were injected with 1 μL of saline or LPS (5 mg/mL) into the hippocampus to evaluate the effect of LPS-induced neuroinflammation on protein homeostasis. The synergic effect of LPS and proteasome inhibition was analyzed in young rats that first received 1 μL of LPS and 24 h later 1 μL (5 mg/mL) of the proteasome inhibitor lactacystin. Animals were sacrificed at different times post-injection and hippocampi isolated and processed for gene expression analysis by real-time polymerase chain reaction; protein expression analysis by western blots; proteasome activity by fluorescence spectroscopy; immunofluorescence analysis by confocal microscopy; and degeneration assay by Fluoro-Jade B staining. LPS injection produced the accumulation of ubiquitinated proteins in hippocampal neurons, increased expression of the E2 ubiquitin-conjugating enzyme UB2L6, decreased proteasome activity and increased immunoproteasome content. However, LPS injection was not sufficient to produce neurodegeneration. The combination of neuroinflammation and proteasome inhibition leads to higher neuronal accumulation of ubiquitinated proteins, predominant expression of pro-apoptotic markers and increased neurodegeneration, when compared with LPS or lactacystin (LT) injection alone. Our results identify neuroinflammation as a risk factor that increases susceptibility to neurodegeneration induced by proteasome inhibition. These results highlight the modulation of neuroinflammation as a mechanism for neuronal protection that could be relevant in situations where both factors are present, such as aging and neurodegenerative diseases.
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影响因子：
3.7
作者：
Mishto M;Bellavista E;Ligorio C;Textoris-Taube K;Santoro A;Giordano M;D'Alfonso S;Listì F;Nacmias B;Cellini E;Leone M;Grimaldi LM;Fenoglio C;Esposito F;Martinelli-Boneschi F;Galimberti D;Scarpini E;Seifert U;Amato MP;Caruso C;Foschini MP;Kloetzel PM;Franceschi C
通讯作者：
Franceschi C
影响因子：
5.3
作者：
Jimenez, Sebastian;Baglietto-Vargas, David;Vitorica, Javier
通讯作者：
Vitorica, Javier
影响因子：
4.7
作者：
Gavilan, M. Paz;Revilla, Elisa;Ruano, Diego
通讯作者：
Ruano, Diego
影响因子：
4.3
作者：
Harry GJ;Kraft AD
通讯作者：
Kraft AD
影响因子：
4.7
作者：
Gavilan, M. Paz;Castano, Angelica;Ruano, Diego
通讯作者：
Ruano, Diego