title: Chronic Pharmacological mGluR5 Inhibition Prevents Cognitive Impairment and Reduces Pathogenesis in an Alzheimer Disease Mouse Model.
abstract: Beta-amyloid (Aβ) oligomers contribute to the pathophysiology of Alzheimer disease (AD), and metabotropic glutamate receptor 5 (mGluR5) has been shown to act as a receptor for both Aβ oligomers and cellular prion proteins. Furthermore, the genetic deletion of mGluR5 in an APPswe/PS1ΔE9 mouse model of AD improves cognitive function and reduces Aβ plaques and Aβ oligomer concentrations. Here, we show that chronic administration of the orally bioavailable mGluR5-selective negative allosteric modulator CTEP, which is similar in structure, potency, and selectivity to Basimglurant (RO4917523), which is currently in phase II clinical development for major depressive disorder and fragile X syndrome, reverses cognitive decline in APPswe/PS1ΔE9 mice and reduces Aβ plaque deposition and soluble Aβ oligomer concentrations in both APPswe/PS1ΔE9 and 3xTg-AD male mice. These findings suggest that CTEP or its analogue Basimglutant might potentially be an effective therapeutic for the treatment of AD patients.
authors.affiliation: University of Ottawa Brain and Mind Institute, Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: Alison
authors.initials: A
authors.lastname: Hamilton
authors.affiliation: Robarts Research Institute, 100 Perth Drive, London, ON N6A 5K8, Canada.
authors.forename: Maryam
authors.initials: M
authors.lastname: Vasefi
authors.affiliation: Robarts Research Institute, 100 Perth Drive, London, ON N6A 5K8, Canada.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Vander Tuin
authors.affiliation: Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada.
authors.forename: Robyn J
authors.initials: RJ
authors.lastname: McQuaid
authors.affiliation: Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada.
authors.forename: Hymie
authors.initials: H
authors.lastname: Anisman
authors.affiliation: University of Ottawa Brain and Mind Institute, Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada. Electronic address: sferguso@uottawa.ca.
authors.forename: Stephen S G
authors.initials: SS
authors.lastname: Ferguson
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D060825:Cognitive Dysfunction / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008568:Memory / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000473:pathology / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C569289:2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine; D016229:Amyloid beta-Peptides; D007093:Imidazoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5