Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice.
Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice.
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发表时间：
2005
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通讯作者：
M. Heneka;M. Sastre;Lucia Dumitrescu-Ozimek;A. Hanke;I. Dewachter;Cuno Kuiperi;K. O’Banion;T. Kloc
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作者：
M. Heneka;M. Sastre;Lucia Dumitrescu-Ozimek;A. Hanke;I. Dewachter;Cuno Kuiperi;K. O’Banion;T. Kloc
阿尔茨海默病患者大脑中的神经性斑块的特征是与胶质细胞介导的炎症反应有关的β-淀粉样蛋白沉积。非类固醇抗炎药(NSAID)治疗降低了阿尔茨海默病的风险，并改善了阿尔茨海默病大脑中小胶质细胞的反应性；然而，这种作用的分子机制尚不清楚。由于几种非甾体抗炎药结合并激活核受体过氧化体增殖物激活受体-伽马(PPARGamma)，从而抑制促炎基因的表达，该受体似乎是一个很好的候选者来介导所观察到的抗炎作用。最近的体外数据表明，非甾体抗炎药通过PPAR-Gamma激活，负性调节小胶质细胞的激活和免疫刺激的淀粉样前体蛋白的处理。我们报道了用PPARγ激动剂吡格列酮或非甾体抗炎药布洛芬对10个月大的APPV717I小鼠进行7天的急性口服治疗，结果导致海马区和皮质中激活的小胶质细胞和反应性星形胶质细胞的数量减少。药物治疗可降低致炎酶COX2和诱导型一氧化氮合酶(INOS)的表达。在抑制炎症标志物的同时，吡格列酮和布洛芬治疗降低了β-分泌酶-1(BACE1)的mRNA和蛋白水平。重要的是，我们观察到Abeta1-42阳性淀粉样蛋白沉积在海马区和皮质的总面积和染色强度显著减少。此外，用吡格列酮治疗的动物显示，可溶性Abeta1-42肽水平降低了27%。这些发现表明，抗炎药物可以迅速起作用，抑制大脑中的炎症反应，并对淀粉样蛋白的形成进行负面调节。
Neuritic plaques in the brain of Alzheimer's disease patients are characterized by beta-amyloid deposits associated with a glia-mediated inflammatory response. Non-steroidal anti-inflammatory drug (NSAID) therapy reduces Alzheimer's disease risk and ameliorates microglial reactivity in Alzheimer's disease brains; however, the molecular mechanisms subserving this effect are not yet clear. Since several NSAIDs bind to and activate the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) which acts to inhibit the expression of proinflammatory genes, this receptor appears a good candidate to mediate the observed anti-inflammatory effects. Recent data in vitro suggested that NSAIDs negatively regulate microglial activation and immunostimulated amyloid precursor protein processing via PPARgamma activation. We report that an acute 7 day oral treatment of 10-month-old APPV717I mice with the PPARgamma agonist pioglitazone or the NSAID ibuprofen resulted in a reduction in the number of activated microglia and reactive astrocytes in the hippocampus and cortex. Drug treatment reduced the expression of the proinflammatory enzymes cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS). In parallel to the suppression of inflammatory markers, pioglitazone and ibuprofen treatment decreased beta-secretase-1 (BACE1) mRNA and protein levels. Importantly, we observed a significant reduction of the total area and staining intensity of Abeta1-42-positive amyloid deposits in the hippocampus and cortex. Additionally, animals treated with pioglitazone revealed a 27% reduction in the levels of soluble Abeta1-42 peptide. These findings demonstrate that anti-inflammatory drugs can act rapidly to inhibit inflammatory responses in the brain and negatively modulate amyloidogenesis.