Multiple forms of Abeta42 are generated from the Abeta42 protein precursor (APP) following cleavage with enzymes known as b- and gamma-secretases. Abeta40 is the most abundant, however Abeta42 is deposited earlier and more consistently than Abeta40 and is therefore more toxic.
Of the NSAIDs tested, meclofenamic acid and flurbiprofen were the most effective at decreasing Abeta42 levels. The authors found that flurbiprofen, currently in clinical trials for the treatment of prostate and colon cancer, directly targets gamma-secretase and the conversion of APP to Abeta42 without inducing toxic gastrointestinal or renal side-effects associated with some NSAIDs.
In their accompanying commentary, Drs. John Cirrito and David Holtzman from Washington University in St. Louis, Missouri comment that "these studies provide exciting new insights and avenues for AD treatment by furthering our understanding of how NSAIDs alter Abeta42 production. While it is not going to be easy, there remains much hope that the amyloid hypothesis of AD will be tested and that truly effective therapies for AD can be developed".
TITLE: NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta42 in vivo
AUTHOR CONTACT:
Todd Golde
Mayo Clinic, Jacksonville, Florida, USA.
Phone: 904-953-2538
Fax: 904-953-7370
Email: tgolde@mayo.edu
View the PDF of this article at: http://www.jci.org/cgi/content/full/112/3/440
ACCOMPANYING COMMENTARY:
Amyloid-beta and Alzheimer disease therapeutics: The devil may be in the details
AUTHOR CONTACT:
David M. Holtzman
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: 314-747-0286
Fax: 314-362-2826
Email: holtzman@neuro.wustl.edu
Journal of Clinical Investigation