title: Targeting glutamatergic and cellular prion protein mechanisms of amyloid β-mediated persistent synaptic plasticity disruption: Longitudinal studies.
abstract: Alzheimer's disease amyloid-β (Aβ) oligomers are synaptotoxic, inappropriately increasing extracellular glutamate concentration and glutamate receptor activation to thereby rapidly disrupt synaptic plasticity. Thus, acutely promoting brain glutamate homeostasis with a blood-based scavenging system, glutamate-oxaloacetate transaminase (GOT), and blocking metabotropic glutamate 5 (mGlu5) receptor or its co-receptor cellular prion protein (PrP), prevent the acute inhibition of long-term potentiation (LTP) by exogenous Aβ. Here, we evaluated the time course of the effects of such interventions in the persistent disruptive effects of Aβ oligomers, either exogenously injected in wild type rats or endogenously generated in transgenic rats that model Alzheimer's disease amyloidosis. We report that repeated, but not acute, systemic administration of recombinant GOT type 1, with or without the glutamate co-substrate oxaloacetate, reversed the persistent deleterious effect of exogenous Aβ on synaptic plasticity. Moreover, similar repetitive treatment reversibly abrogated the inhibition of LTP monitored longitudinally in freely behaving transgenic rats. Remarkably, brief repeated treatment with an mGlu5 receptor antagonist, basimglurant, or an antibody that prevents Aβ oligomer binding to PrP, ICSM35, also had similar reversible ameliorative effects in the transgenic rat model. Overall, the present findings support the ongoing development of therapeutics for early Alzheimer's disease based on these complementary approaches.
authors.affiliation: Department of Pharmacology & Therapeutics, and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Center for Neurological Diseases (NCRC-ND), Beijing, China.
authors.forename: Dainan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology & Therapeutics, and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland. Electronic address: qiyi@tcd.ie.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Pharmacology & Therapeutics, and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Igor
authors.initials: I
authors.lastname: Klyubin
authors.affiliation: Department of Pharmacology & Therapeutics, and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Tomas
authors.initials: T
authors.lastname: Ondrejcak
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Sarell
authors.affiliation: Department of Pharmacology and Therapeutics, Department of Neurology and Neurosurgery, Department of Anatomy and Cell Biology, McGill University, Montreal, Canada.
authors.forename: A Claudio
authors.initials: AC
authors.lastname: Cuello
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.affiliation: Department of Pharmacology & Therapeutics, and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland. Electronic address: mrowan@tcd.ie.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rowan
mesh_terms: D016229:Amyloid beta-Peptides / Q000276:immunology / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000097:blood / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D024443:Aspartate Aminotransferase, Cytoplasmic / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D000072002:Prion Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D055647:Rats, Transgenic; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014851:Wakefulness
chemical_list: C569289:2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine; C000596770:2-chloro-4-(1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl)pyridine; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D007093:Imidazoles; D010446:Peptide Fragments; D000072002:Prion Proteins; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; C075222:amyloid beta-protein (1-42); D024443:Aspartate Aminotransferase, Cytoplasmic
keywords: APP transgenic rat; Alzheimer's disease; Glutamate-oxalate transaminase; Long-term potentiation; Metabotropic glutamate receptor 5