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

• DOI: 10.1186/s40478-014-0175-x
• Publication Date: 2014-12-23T06:19:09Z
• Authors: Yingjie Qi; Igor Klyubin; Sarah C Harney; NengWei Hu; William K Cullen; Marianne K Grant; Julia Steffen; Edward N Wilson; Sonia Do Carmo; Stefan Remy; Martin Fuhrmann; Karen H Ashe; A Claudio Cuello; Michael J Rowan
• Keywords: N-(3-(2-amino-4a,5,7,7a-tetrahydro-4H-furo(3,4-d)(1,3)thiazin-7a-yl)-4-fluorophenyl)-5-fluoropicolinamide; Male; 0301 basic medicine; drug effects [Hippocampus]; MRK 560; hippocampus; pharmacology [Antibodies]; Bace1 protein, rat; aspartic proteinase; Long-Term Potentiation; metabolism [Hippocampus]; amyloid precursor protein; antagonists & inhibitors [Amyloid Precursor Protein Secretases]; Wistar rat; animal behavior; Hippocampus; immunology; Amyloid beta-Protein Precursor; pharmacology [Sulfonamides]; Heterocyclic Compounds; antibody; Aspartic Acid Endopeptidases; rat; animal; genetics; pharmacology [Heterocyclic Compounds, 2-Ring]; long term potentiation; Picolinic Acids; pathophysiology; drug effects [Synaptic Transmission]; Sulfonamides; Behavior, Animal; Age Factors; transgenic rat; antagonists & inhibitors [Aspartic Acid Endopeptidases]; immunology [Amyloid beta-Peptides]; 3. Good health; physiology [Behavior, Animal]; genetics [Amyloid beta-Protein Precursor]; pharmacology [Picolinic Acids]; Alzheimer disease; Rats, Transgenic; secretase; 610; metabolism [Amyloid beta-Peptides]; Bace protein; physiopathology [Alzheimer Disease]; Heterocyclic Compounds, 2-Ring; Antibodies; 03 medical and health sciences; male; Alzheimer Disease; sulfonamide; synaptic transmission; Animals; Humans; human; ddc:610; Rats, Wistar; immunology [Amyloid beta-Protein Precursor]; antagonists and inhibitors; 2-Ring; Behavior; Amyloid beta-Peptides; disease model; Research; fused heterocyclic rings; picolinic acid derivative; Rats; Disease Models, Animal; age; physiology [Synaptic Transmission]; amyloid beta protein; drug effects; physiology; Disease Models; physiopathology [Hippocampus]; drug effects [Long-Term Potentiation]; physiology [Long-Term Potentiation]; Amyloid Precursor Protein Secretases; metabolism

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.