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.
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Acknowledgements
These studies were funded by the US National Institutes of Health National Institute on Aging (P01 AG20206 to E.K. and T.G.). Additional resources from the Mayo Foundation provided by a gift from R. and C. Smith were used to support the Tg2576 mouse colony that provided the mice used in these studies. J.E. was supported by John Douglas French Foundation fellowship grant. S.S. was supported by a US National Institutes of Health training grant (T 32 AG00216). We thank L. Marnett, K. Zavitz and R. Slade for providing compounds; K. Jessing and J. Scott Patton for analyzing celecoxib levels; and S. Younkin, L. Younkin, D. Yaeger, B. Bone, T. Brehm-Gibson and C. Eckman for their assistance in developing anti-Aβ antibodies and novel Aβ ELISAs.
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Edward H. Koo and Todd E.Golde are co-inventors on a patent application with claims pertaining to the use of Aβ42 lowering NSAIDs and NSAID derivatives in Alzheimer disease.
Supplementary information
Supplementary Fig. 1
Dose response of multiple COX-2 inhibitors compounds in H4 cells. (PDF 132 kb)
Supplementary Fig. 2
COX-2 selective derivatives of Indomethacin and Meclofenamic acid raise Aβ42. (PDF 133 kb)
Supplementary Fig. 3
Extended dose-response studies of fenofibrate, celecoxib, GGPP and FPP. (PDF 124 kb)
Supplementary Fig. 4
Effects of celecoxib, fenofibrate and GGPP on CTFγ production in vitro. (PDF 92 kb)
Supplementary Fig. 5
Distinct effects of fenofibrate, celecoxib and FT-1 on APP, sAPP CTFα and CTFβ levels in H4 cells. (PDF 122 kb)
Supplementary Fig. 6
Scatter plots of Aβ40 (x-axis) and Aβ42 (y-axis) levels of animals dosed with celecoxib and FT-1 at either 50 mg/kg/day (50) or 100 mg/kg/day (100). (PDF 121 kb)
Supplementary Table 1
Indomethacin derivatives (PDF 80 kb)
Supplementary Table 2
Meclofenamic acid derivatives (PDF 51 kb)
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Kukar, T., Murphy, M., Eriksen, J. et al. Diverse compounds mimic Alzheimer disease–causing mutations by augmenting Aβ42 production. Nat Med 11, 545–550 (2005). https://doi.org/10.1038/nm1235
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DOI: https://doi.org/10.1038/nm1235
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