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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Supplementary information
Supplementary Fig. 1
Effects of NSAIDs on Aβ secretion. (PDF 366 kb)
Supplementary Fig. 2
NSAIDs do not inhibit BACE or γ-secretase. (PDF 361 kb)
Supplementary Fig. 3
FLIM assay of proximity between APP and PS1. (PDF 305 kb)
Supplementary Table 1
Some NSAIDs change PS1 conformation assessed by FLIM. (PDF 21 kb)
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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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DOI: https://doi.org/10.1038/nm1112
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