FDA-approved drugs shown to lower Alzheimer disease–related protein levels in mice

Alzhemier disease (AD) is characterized by the progressive accumulation of amyloid b protein (Abeta) in areas of the brain serving cognitive functions such as memory and language. In 2001, Todd Golde and colleagues demonstrated that three commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) were capable of selectively lowering the levels of Abeta42 (an isoform of the Abeta protein) in mice. In the August 1 issue of the Journal of Clinical Investigation, Golde and colleagues from the Mayo Clinic in Jacksonville, Florida, extend their previous studies and report that of 20 commonly used NSAIDs, 8 FDA-approved drugs successfully lowered Abeta42 levels in mice at doses achievable in humans.

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

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