Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production

被引:238
作者
Kukar, T
Murphy, MP
Eriksen, JL
Sagi, SA
Weggen, S
Smith, TE
Ladd, T
Khan, MA
Kache, R
Beard, J
Dodson, M
Merit, S
Ozols, VV
Anastasiadis, PZ
Das, P
Fauq, A
Koo, EH
Golde, TE
机构
[1] Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA
[2] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
[3] Mayo Clin, Coll Med, Ctr Comprehens Canc, Jacksonville, FL 32224 USA
关键词
D O I
10.1038/nm1235
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:545 / 550
页数:6
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