title: R-flurbiprofen improves tau, but not Aß pathology in a triple transgenic model of Alzheimer's disease.
abstract: We have previously reported that chronic ibuprofen treatment improves cognition and decreases intracellular Aß and phosphorylated-tau levels in 3xTg-AD mice. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that independently of its anti-inflammatory effects has anti-amyloidogenic activity as a gamma-secretase modulator (GSM) and both activities have the potential to decrease Aß pathology. To further understand the effects of NSAIDs in 3xTg-AD mice, we treated 3xTg-AD mice with R-flurbiprofen, an enantiomer of the NSAID flurbiprofen that maintains the GSM activity but has greatly reduced anti-inflammatory activity, and analyzed its effect on cognition, Aß, tau, and the neurochemical profile of the hippocampus. 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 immunostained with AT8 and PHF-1 antibodies. No significant changes in the level of Aß (using 6E10 and NU-1 antibodies) were detected. Using magnetic resonance spectroscopy (MRS) we found that R-flurbiprofen treatment 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. We also found an inverse correlation between the concentration of glutamate and learning across all the mice in the study. 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.
authors.affiliation: Research/GRECC, VA Boston Healthcare System, Boston, MA.|Department of Biochemistry, Boston University School of Medicine, Boston, MA.
authors.forename: Isabel
authors.initials: I
authors.lastname: Carreras
authors.affiliation: Research/GRECC, VA Boston Healthcare System, Boston, MA.|Department of Neurology, Boston University School of Medicine, Boston, MA.|Department of Pathology, Boston University School of Medicine, Boston, MA.
authors.forename: Ann C
authors.initials: AC
authors.lastname: McKee
authors.affiliation: A.A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors.forename: Ji-Kyung
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Research/GRECC, VA Boston Healthcare System, Boston, MA.|Department of Neurology, Boston University School of Medicine, Boston, MA.
authors.forename: Nurgul
authors.initials: N
authors.lastname: Aytan
authors.affiliation: Research/GRECC, VA Boston Healthcare System, Boston, MA.|Department of Neurology, Boston University School of Medicine, Boston, MA.|Department of Pathology, Boston University School of Medicine, Boston, MA.
authors.forename: Neil W
authors.initials: NW
authors.lastname: Kowall
authors.affiliation: A.A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Jenkins
authors.affiliation: Research/GRECC, VA Boston Healthcare System, Boston, MA.|Department of Neurology, Boston University School of Medicine, Boston, MA.|A.A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors.forename: Alpaslan
authors.initials: A
authors.lastname: Dedeoglu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004195:Disease Models, Animal; D005480:Flurbiprofen / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D009682:Magnetic Resonance Spectroscopy; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D016875:tau Proteins / Q000187:drug effects* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016875:tau Proteins; D005973:Glutamine; D018698:Glutamic Acid; D005480:Flurbiprofen
keywords: 3xTg-AD mice; Aß; Hyperphosphorylated tau; Magnetic resonance spectroscopy; R-flurbiprofen