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

Thomas Kukar, Michael Paul Murphy, Jason L. Eriksen, Sarah A. Sagi, Sascha Weggen, Tawnya E. Smith, Thomas Ladd, Murad A. Khan, Rajashaker Kache, Jenny Beard, Mark Dodson, Sami Merit, Victor V. Ozols, Panos Z. Anastasiadis, Pritam Das, Abdul Fauq, Edward H. Koo, Todd E. Golde

Research output: Contribution to journalArticle

246 Scopus citations

Abstract

Increased Aβ42 production has been linked to the development of Alzheimer disease. We now identify a number of compounds that raise Aβ42. Among the more potent Aβ42-raising agents identified are fenofibrate, an antilipidemic agent, and celecoxib, a COX-2-selective NSAID. Many COX-2-selective NSAIDs tested raised Aβ42, including multiple COX-2-selective derivatives of two Aβ42-lowering NSAIDs. Compounds devoid of COX activity and the endogenous isoprenoids FPP and GGPP also raised Aβ42. These compounds seem to target the γ-secretase complex, increasing γ-secretase-catalyzed production of Aβ42 in vitro. Short-term in vivo studies show that two Aβ42-raising compounds increase Aβ42 levels in the brains of mice. The elevations in Aβ42 by these compounds are comparable to the increases in Aβ42 induced by Alzheimer disease-causing mutations in the genes encoding amyloid β protein precursor and presenilins, raising the possibility that exogenous compounds or naturally occurring isoprenoids might increase Aβ42 production in humans.

Original languageEnglish (US)
Pages (from-to)545-550
Number of pages6
JournalNature Medicine
Volume11
Issue number5
DOIs
StatePublished - May 1 2005

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kukar, T., Murphy, M. P., Eriksen, J. L., Sagi, S. A., Weggen, S., Smith, T. E., Ladd, T., Khan, M. A., Kache, R., Beard, J., Dodson, M., Merit, S., Ozols, V. V., Anastasiadis, P. Z., Das, P., Fauq, A., Koo, E. H., & Golde, T. E. (2005). Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production. Nature Medicine, 11(5), 545-550. https://doi.org/10.1038/nm1235