title: Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Aß agents.
abstract: Long before synaptic loss occurs in Alzheimer's disease significant harbingers of disease may be detected at the functional level. Here we examined if synaptic long-term potentiation is selectively disrupted prior to extracellular deposition of Aß in a very complete model of Alzheimer's disease amyloidosis, the McGill-R-Thy1-APP transgenic rat. Longitudinal studies in freely behaving animals revealed an age-dependent, relatively rapid-onset and persistent inhibition of long-term potentiation without a change in baseline synaptic transmission in the CA1 area of the hippocampus. Thus the ability of a standard 200 Hz conditioning protocol to induce significant NMDA receptor-dependent short- and long-term potentiation was lost at about 3.5 months of age and this deficit persisted for at least another 2-3 months, when plaques start to appear. Consistent with in vitro evidence for a causal role of a selective reduction in NMDA receptor-mediated synaptic currents, the deficit in synaptic plasticity in vivo was associated with a reduction in the synaptic burst response to the conditioning stimulation and was overcome using stronger 400 Hz stimulation. Moreover, intracerebroventricular treatment for 3 days with an N-terminally directed monoclonal anti- human Aß antibody, McSA1, transiently reversed the impairment of synaptic plasticity. Similar brief treatment with the BACE1 inhibitor LY2886721 or the γ-secretase inhibitor MRK-560 was found to have a comparable short-lived ameliorative effect when tracked in individual rats. These findings provide strong evidence that endogenously generated human Aß selectively disrupts the induction of long-term potentiation in a manner that enables potential therapeutic options to be assessed longitudinally at the pre-plaque stage of Alzheimer's disease amyloidosis.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Qi
authors.forename: Igor
authors.initials: I
authors.lastname: Klyubin
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Harney
authors.forename: NengWei
authors.initials: N
authors.lastname: Hu
authors.forename: William K
authors.initials: WK
authors.lastname: Cullen
authors.forename: Marianne K
authors.initials: MK
authors.lastname: Grant
authors.forename: Julia
authors.initials: J
authors.lastname: Steffen
authors.forename: Edward N
authors.initials: EN
authors.lastname: Wilson
authors.forename: Sonia
authors.initials: S
authors.lastname: Do Carmo
authors.forename: Stefan
authors.initials: S
authors.lastname: Remy
authors.forename: Martin
authors.initials: M
authors.lastname: Fuhrmann
authors.forename: Karen H
authors.initials: KH
authors.lastname: Ashe
authors.forename: A Claudio
authors.initials: AC
authors.lastname: Cuello
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rowan
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010848:Picolinic Acids / Q000494:pharmacology; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D006574:Heterocyclic Compounds, 2-Ring; C510791:MRK 560; C000596181:N-(3-(2-amino-4a,5,7,7a-tetrahydro-4H-furo(3,4-d)(1,3)thiazin-7a-yl)-4-fluorophenyl)-5-fluoropicolinamide; D010848:Picolinic Acids; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat