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

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.