Inhibitory effect of minocycline on amyloid β fibril formation and human microglial activation
Inhibitory effect of minocycline on amyloid β fibril formation and human microglial activation
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DOI：
10.1002/glia.20268
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发表时间：
2006-02-01
期刊：
影响因子：
6.2
通讯作者：
Veerhuis, R
中科院分区：
文献类型：
--
作者：
Familian, A;Boshuizen, RS;Veerhuis, R
米诺环素是抗生素四环素的衍生物，在各种神经退行性疾病模型中显示出神经保护特性，并且由于其相对安全性和耐受性，现在用于临床试验。米诺环素通过血脑屏障，并被认为是抑制小胶质细胞活化。在阿尔茨海默病的大脑中，许多蛋白质，包括血清淀粉样蛋白P组分（SAP）和补体因子如C1 q，积累在淀粉样蛋白β（A β）斑块中。在先前的研究中，发现SAP和C1 q是A β斑块中活化的小胶质细胞聚集所必需的。此外，SAP和C1 q增强A β纤维形成和A β介导的细胞因子释放的人小胶质细胞在体外。在本研究中，我们报告四环素和米诺环素剂量依赖性地减少TNF-α和IL-6释放成人小胶质细胞刺激后，与A β，SAP和C1 q的组合。此外，米诺环素和四环素在较小程度上抑制A β的原纤维形成，如在基于硫磺素-S的荧光试验中所测定的。单独使用A β以及A β与SAP和C1 q联合使用时均观察到这种抑制作用。我们的数据表明，米诺环素和四环素在耐受剂量可以抑制人类小胶质细胞的激活。这种活性部分通过抑制（SAP和C1 q增强的）A β原纤维形成来发挥。(C)2005 Wiley-Liss，Inc.
Minocycline, a derivative of the antibiotic tetracycline, displays neuroprotective properties in various models of neurodegenerative diseases and is now used in clinical trials, because of its relative safety and tolerability. Minocycline passes the blood-brain barrier and is presumed to inhibit microglial activation. In Alzheimer's disease brain, a number of proteins, including serum amyloid P component (SAP) and complement factors such as C1q, accumulate in amyloid beta (A beta) plaques. In a previous study, SAP and C1q were found to be required for clustering of activated microglia in A beta plaques. Furthermore, SAP and C1q enhanced A beta fibril formation and A beta mediated cytokine release by human microglia in vitro. In the present study, we report that tetracycline and minocycline dose-dependently reduce TNF-alpha and IL-6 release by adult human microglia upon stimulation with a combination of A beta, SAP, and C1q. In addition, minocycline and to a lesser extent tetracycline inhibit fibril formation of A beta as determined in a thioflavin-S-based fluorescence test. This inhibitory effect was observed with A beta alone as well as with A beta in combination with SAP and C1q. Our data suggest that minocycline and tetracycline at tolerable doses can inhibit human microglial activation. This activity in part is exerted by inhibition of (SAP and C1q enhanced) A beta fibril formation. (C) 2005 Wiley-Liss, Inc.