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R-flurbiprofen improves tau, but not Aβ pathology in a triple transgenic model of Alzheimer's disease


Year of Publication:
Contact PI Name:
Alpaslan Dedeoglu
Contact PI Affiliation:
Research and Development Service, VA Boston Healthcare System, Boston, Massachusetts, USA
I. Carreras, A.C. McKee, J.K. Choi, N. Aytan, N.W. Kowall, B.G. Jenkins
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
United States Department of Veterans Affairs (VA)
Study Goal and Principal Findings:

The study investigated effects of gamma secretase modulator R-flurbiprofen on AD neuropathology in 3xTg-AD mice. Multiple epidemiological studies have shown that treatment with NSAIDs was associated with a reduced risk of developing AD. However, the results of pharmacological studies with anti-inflammatory agents have been inconsistent in both mice and humans. Interest in the effects of NSAIDs on AD grew faster after a subset of NSAIDs was found to decrease the production of the more amyloidogenic Aß42 peptide at the expense of shorter and less toxic Aß forms, which appears to involve the allosteric modulation of γ-secretase. Treatment with R-flurbiprofen, an enantiomer of flurbiprofen that maintains the GSM activity in vitro and in vivo, but lacks antiinflammatory activity, attenuated learning impairments and lowered Aß42 in vivo. In this study, treatment with R-flurbiprofen from 5 to 7 months of age resulted in improved cognition on the radial arm water maze (RAWM) test and decreased the level of hyperphosphorylated tau. No significant changes in the level of Aß were detected. Using magnetic resonance spectroscopy (MRS), R-flurbiprofen decreased the elevated level of glutamine in 3xTg-AD mice down to the level detected in non-transgenic mice. Glutamine levels correlated with PHF-1 immunostained hyperphosphorylated tau. There was an inverse correlation between the concentration of glutamate and learning across all the mice in the study. This study suggests that glutamine and glutamate, neurochemicals that shuttles between neurons and astrocytes to maintain glutamate homeostasis in the synapses, deserve further attention as MR markers of cognitive function.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
gamma Secretase
Therapeutic Notes:
R-Flurbiprofen is the R-enantiomer of the NSAID Flurbiprofen. It is not a cyclooxygenase (COX 1/COX 2) inhibitor. R-Flurbiprofen has recently been shown to modulate gamma secretase and selectively lower levels of Aβ42 and amyloid pathology in vivo. R-Flurbiprofen also modulates NFκB signaling pathways.

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Radial Arm Water Maze
beta Amyloid Deposits
Tau Protein
Brain-beta Amyloid Peptides
Magnetic Resonance Spectroscopy (MRS)
Drug Concentration-Brain
Drug Concentration-Plasma
Target Engagement (Reduction beta Amyloid Peptide 42-Brain)
Body Weight