Bi Xiaoning, Baudry Michel, Liu Jihua, Yao Yueqin, Fu Lawrence, Brucher Fernando, Lynch Gary
Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, CA 92617-1695, USA.
J Biol Chem. 2004 Nov 12;279(46):48238-45. doi: 10.1074/jbc.M405442200. Epub 2004 Sep 9.
Inflammatory responses involving microglia, the resident macrophages of the brain, are thought to contribute importantly to the progression of Alzheimer's disease (AD) and possibly other neurodegenerative disorders. The present study tested whether the mevalonate-isoprenoid biosynthesis pathway, which affects inflammation in many types of tissues, tonically regulates microglial activation. This question takes on added significance given the potential use of statins, drugs that block the rate-limiting step (3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase)) in mevalonate and cholesterol synthesis, in AD treatment. Both mevastatin and simvastatin caused a concentration- and time-dependent activation of microglia in cultured rat hippocampal slices. This response consisted of a transformation of the cells from a typical resting configuration to an amoeboid, macrophage-like morphology, increased expression of a macrophage antigen, and up-regulation of the cytokine tumor necrosis factor-alpha. Evidence for proliferation was also obtained. Statin-induced microglial changes were blocked by mevalonate but not by cholesterol, indicating that they were probably due to suppression of isoprenoid synthesis. In accord with this, the statin effects were absent in slices co-incubated with geranylgeranyl pyrophosphate, a mevalonate product that provides for the prenylation of Rho GTPases. Finally, PD98089, a compound that blocks activation of extracellularly regulated kinases1/2, suppressed statin-induced up-regulation of tumor necrosis factor-alpha but had little effect on microglial transformation. These results suggest that 1) the mevalonate-isoprenoid pathway is involved in regulating microglial morphology and in controlling expression of certain cytokines and 2) statins have the potential for enhancing a component of AD with uncertain relationships to other features of the disease.
涉及小胶质细胞（大脑中的常驻巨噬细胞）的炎症反应被认为在阿尔茨海默病（AD）以及可能的其他神经退行性疾病的进展中起重要作用。本研究测试了甲羟戊酸 - 类异戊二烯生物合成途径，该途径影响多种组织中的炎症，是否持续调节小胶质细胞的激活。鉴于他汀类药物（阻断甲羟戊酸和胆固醇合成中的限速步骤（3 - 羟基 - 3 - 甲基戊二酰辅酶A还原酶（HMG - CoA还原酶））的药物）在AD治疗中的潜在用途，这个问题具有额外的重要性。美伐他汀和辛伐他汀均在培养的大鼠海马切片中引起小胶质细胞浓度和时间依赖性的激活。这种反应包括细胞从典型的静止形态转变为变形虫样、巨噬细胞样形态，巨噬细胞抗原表达增加，以及细胞因子肿瘤坏死因子 - α的上调。还获得了增殖的证据。他汀类药物诱导的小胶质细胞变化被甲羟戊酸阻断，但未被胆固醇阻断，表明它们可能是由于类异戊二烯合成的抑制。与此一致的是，在与香叶基香叶基焦磷酸（一种为Rho GTPases提供异戊二烯化的甲羟戊酸产物）共同孵育的切片中没有他汀类药物的作用。最后，PD98089（一种阻断细胞外调节激酶1/2激活的化合物）抑制了他汀类药物诱导的肿瘤坏死因子 - α上调，但对小胶质细胞转化影响很小。这些结果表明：1）甲羟戊酸 - 类异戊二烯途径参与调节小胶质细胞形态并控制某些细胞因子的表达；2）他汀类药物有可能增强AD的一个组成部分，而与该疾病的其他特征关系不确定。
