Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production
Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production
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DOI：
10.1038/nm1235
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发表时间：
2005-05-01
期刊：
影响因子：
82.9
通讯作者：
Golde, TE
中科院分区：
文献类型：
--
作者：
Kukar, T;Murphy, MP;Golde, TE
A β 42产生的增加与阿尔茨海默病的发展有关。我们现在确定了一些提高A β 42的化合物。在更有效的A β 42升高剂中，确定了非诺贝特，一种抗风湿药，和塞来昔布，一种考克斯-2-选择性NSAID。测试的许多考克斯-2选择性NSAID升高A β 42，包括两种降低A β 42的NSAID的多种考克斯-2选择性衍生物。缺乏考克斯活性的化合物和内源性类异戊二烯FPP和GGPP也升高A β 42。这些化合物似乎靶向γ-分泌酶复合物，在体外增加γ-分泌酶催化的A β 42的产生。短期体内研究表明，两种A β 42升高化合物可增加小鼠大脑中的A β 42水平。这些化合物引起的A β 42升高与编码淀粉样β蛋白前体和早老素的基因中引起阿尔茨海默病的突变诱导的A β 42增加相当，这增加了外源性化合物或天然存在的类异戊二烯可能增加人类A β 42产生的可能性。
Increased A beta 42 production has been linked to the development of Alzheimer disease. We now identify a number of compounds that raise A beta 42. Among the more potent A beta 42-raising agents identified are fenofibrate, an antilipidemic agent, and celecoxib, a COX-2-selective NSAID. Many COX-2-selective NSAIDs tested raised A beta 42, including multiple COX-2-selective derivatives of two A beta 42-lowering NSAIDs. Compounds devoid of COX activity and the endogenous isoprenoids FPP and GGPP also raised A beta 42. These compounds seem to target the gamma-secretase complex, increasing gamma-secretase-catalyzed production of A beta 42 in vitro. Short-term in vivo studies show that two A beta 42-raising compounds increase A beta 42 levels in the brains of mice. The elevations in A beta 42 by these compounds are comparable to the increases in A beta 42 induced by Alzheimer disease-causing mutations in the genes encoding amyloid beta protein precursor and presenilins, raising the possibility that exogenous compounds or naturally occurring isoprenoids might increase A beta 42 production in humans.