Nonsteroidal anti-inflammatory drugs lower Aβ42 and change presenilin 1 conformation (original) (raw)

Nature Medicine volume 10, pages 1065–1066 (2004)Cite this article

Abstract

Recent reports suggest that some commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) unexpectedly shift the cleavage products of amyloid precursor protein (APP) to shorter, less fibrillogenic forms, although the underlying mechanism remains unknown. We now demonstrate, using a fluorescence resonance energy transfer method, that Aβ42-lowering NSAIDs specifically affect the proximity between APP and presenilin 1 and alter presenilin 1 conformation both in vitro and in vivo, suggesting a novel allosteric mechanism of action.

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Acknowledgements

We thank T. Südhof (University of Texas, Southwestern Medical Center) for the APP-Gal4 constructs, D. Selkoe and M. Wolfe (Brigham and Women's Hospital, Boston, Massachusetts) for PS1 antibodies, and WPE-III-31C and DAPT and H. Fukumoto (Takeda Industries, Osaka, Japan) for assistance with the Aβ ELISAs. This study was supported by US National Institutes of Health AG15379, a Pioneer Award from the Alzheimer Association (B.T.H.), a Hoffmann Fellowship (A.L.), NIH EB00768 (B.J.B.) and a Paul Beeson Physician Faculty Scholar in Aging Research Award (M.P.F).

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Authors and Affiliations

  1. Alzheimer Research Unit, Massachusetts General Hospital, 114 16th St, Charlestown, 02129, Massachusetts, USA
    Alberto Lleó, Oksana Berezovska, Lauren Herl, Susan Raju, Amy Deng, Brian J Bacskai, Matthew P Frosch, Michael Irizarry & Bradley T Hyman

Authors

  1. Alberto Lleó
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  2. Oksana Berezovska
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  3. Lauren Herl
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  4. Susan Raju
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  5. Amy Deng
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  6. Brian J Bacskai
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  7. Matthew P Frosch
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  8. Michael Irizarry
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  9. Bradley T Hyman
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Correspondence toBradley T Hyman.

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The authors declare no competing financial interests.

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Lleó, A., Berezovska, O., Herl, L. et al. Nonsteroidal anti-inflammatory drugs lower Aβ42 and change presenilin 1 conformation.Nat Med 10, 1065–1066 (2004). https://doi.org/10.1038/nm1112

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