title: Proneurogenic Group II mGluR antagonist improves learning and reduces anxiety in Alzheimer Aβ oligomer mouse.
abstract: Proneurogenic compounds have recently shown promise in some mouse models of Alzheimer's pathology. Antagonists at Group II metabotropic glutamate receptors (Group II mGluR: mGlu2, mGlu3) are reported to stimulate neurogenesis. Agonists at those receptors trigger γ-secretase-inhibitor-sensitive biogenesis of Aβ42 peptides from isolated synaptic terminals, which is selectively suppressed by antagonist pretreatment. We have assessed the therapeutic potential of chronic pharmacological inhibition of Group II mGluR in Dutch APP (Alzheimer's amyloid precursor protein E693Q) transgenic mice that accumulate Dutch amyloid-β (Aβ) oligomers but never develop Aβ plaques. BCI-838 is a clinically well-tolerated, orally bioavailable, investigational prodrug that delivers to the brain BCI-632, the active Group II mGluR antagonist metabolite. Dutch Aβ-oligomer-forming APP transgenic mice (APP E693Q) were dosed with BCI-838 for 3 months. Chronic treatment with BCI-838 was associated with reversal of transgene-related amnestic behavior, reduction in anxiety, reduction in levels of brain Aβ monomers and oligomers, and stimulation of hippocampal neurogenesis. Group II mGluR inhibition may offer a unique package of relevant properties as an Alzheimer's disease therapeutic or prophylactic by providing both attenuation of neuropathology and stimulation of repair.
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Steele
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Clemenson
authors.affiliation: BrainCells, San Diego, CA, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Carter
authors.affiliation: BrainCells, San Diego, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Treuner
authors.affiliation: BrainCells, San Diego, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Gadient
authors.affiliation: BrainCells, San Diego, CA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Wedel
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Glabe
authors.affiliation: BrainCells, San Diego, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Barlow
authors.affiliation: 1] Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Ehrlich
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: F H
authors.initials: FH
authors.lastname: Gage
authors.affiliation: 1] Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA [3] James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gandy
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007858:Learning / Q000187:drug effects* / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D011619:Psychotropic Drugs / Q000737:chemistry / Q000494:pharmacology*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011619:Psychotropic Drugs; D018094:Receptors, Metabotropic Glutamate
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