Nature Medicine
11, 545 - 550 (2005)
Published online: 17 April 2005; | doi:10.1038/nm1235
Diverse compounds mimic Alzheimer
disease−causing mutations by augmenting A 42 productionThomas Kukar1, 5, Michael Paul Murphy1, 4, 5, Jason L Eriksen1, 5, Sarah A Sagi2, 5, Sascha Weggen2, 4, Tawnya E Smith1, Thomas Ladd1, Murad A Khan1, Rajashaker Kache1, Jenny Beard1, Mark Dodson1, Sami Merit1, Victor V Ozols1, Panos Z Anastasiadis3, Pritam Das1, Abdul Fauq1, Edward H Koo2
& Todd E Golde11
Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA. 2
Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. 3
Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA. 4
Present addresses: Department of Molecular and Cellular Biochemistry, University of Kentucky, 211-Sanders Brown Center on Aging, Lexington, Kentucky 40536, USA (M.P.M.). Instutute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University of Mainz, Duesbergweg 6, Mainz 55099, Germany (S.W.). 5
These authors contributed equally to this work.
Correspondence should be addressed to Todd E Golde tgolde@mayo.eduIncreased A 42 production has been linked to the development of Alzheimer disease. We now identify a number of compounds that raise A42. Among the more potent A42-raising agents identified are fenofibrate, an antilipidemic agent, and celecoxib, a COX-2−selective NSAID. Many COX-2−selective NSAIDs tested raised A42, including multiple COX-2−selective derivatives of two A42-lowering NSAIDs. Compounds devoid of COX activity and the endogenous isoprenoids FPP and GGPP also raised A42. These compounds seem to target the  -secretase complex, increasing -secretase−catalyzed production of A42 in vitro. Short-term in vivo studies show that two A42-raising compounds increase A42 levels in the brains of mice. The elevations in A42 by these compounds are comparable to the increases in A42 induced by Alzheimer disease−causing mutations in the genes encoding amyloid protein precursor and presenilins, raising the possibility that exogenous compounds or naturally occurring isoprenoids might increase A42 production in humans.
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