title: Time-dependent reversal of synaptic plasticity induced by physiological concentrations of oligomeric Aβ42: an early index of Alzheimer's disease.
abstract: The oligomeric amyloid-β (Aβ) peptide is thought to contribute to the subtle amnesic changes in Alzheimer's disease (AD) by causing synaptic dysfunction. Here, we examined the time course of synaptic changes in mouse hippocampal neurons following exposure to Aβ42 at picomolar concentrations, mimicking its physiological levels in the brain. We found opposite effects of the peptide with short exposures in the range of minutes enhancing synaptic plasticity, and longer exposures lasting several hours reducing it. The plasticity reduction was concomitant with an increase in the basal frequency of spontaneous neurotransmitter release, a higher basal number of functional presynaptic release sites, and a redistribution of synaptic proteins including the vesicle-associated proteins synapsin I, synaptophysin, and the post-synaptic glutamate receptor I. These synaptic alterations were mediated by cytoskeletal changes involving actin polymerization and p38 mitogen-activated protein kinase. These in vitro findings were confirmed in vivo with short hippocampal infusions of picomolar Aβ enhancing contextual memory and prolonged infusions impairing it. Our findings provide a model for initiation of synaptic dysfunction whereby exposure to physiologic levels of Aβ for a prolonged period of time causes microstructural changes at the synapse which result in increased transmitter release, failure of synaptic plasticity, and memory loss.
authors: Department of Pathology &Cell Biology, Columbia University, New York, NY, 10032, USA.|The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, 10032, USA.|Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria.
authors: Peter
authors: P
authors: Koppensteiner
authors: Department of Pathology &Cell Biology, Columbia University, New York, NY, 10032, USA.|The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, 10032, USA.
authors: Fabrizio
authors: F
authors: Trinchese
authors: Department of Pathology &Cell Biology, Columbia University, New York, NY, 10032, USA.|The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, 10032, USA.
authors: Mauro
authors: M
authors: Fà
authors: Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, 95125 Italy.
authors: Daniela
authors: D
authors: Puzzo
authors: Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, 95125 Italy.
authors: Walter
authors: W
authors: Gulisano
authors: Department of Pathology &Cell Biology, Columbia University, New York, NY, 10032, USA.|The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, 10032, USA.
authors: Shijun
authors: S
authors: Yan
authors: Department of Pathology &Cell Biology, Columbia University, New York, NY, 10032, USA.|The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, 10032, USA.
authors: Arthur
authors: A
authors: Poussin
authors: Department of Pathology &Cell Biology, Columbia University, New York, NY, 10032, USA.|The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, 10032, USA.
authors: Shumin
authors: S
authors: Liu
authors: Department of Pathology &Cell Biology, Columbia University, New York, NY, 10032, USA.|The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, 10032, USA.
authors: Ian
authors: I
authors: Orozco
authors: Department of Pathology &Cell Biology, Columbia University, New York, NY, 10032, USA.|The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, 10032, USA.
authors: Elena
authors: E
authors: Dale
authors: Department of Pathology &Cell Biology, Columbia University, New York, NY, 10032, USA.|The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, 10032, USA.
authors: Andrew F
authors: AF
authors: Teich
authors: Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, 95125 Italy.
authors: Agostino
authors: A
authors: Palmeri
authors: Department of Psychiatry, NYU School of Medicine, New York 10016, USA.
authors: Ipe
authors: I
authors: Ninan
authors: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria.
authors: Stefan
authors: S
authors: Boehm
authors: Department of Pathology &Cell Biology, Columbia University, New York, NY, 10032, USA.|The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, 10032, USA.
authors: Ottavio
authors: O
authors: Arancio
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008569:Memory Disorders / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects; D061251:Primary Cell Culture; D055503:Protein Multimerization; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000187:drug effects; D016704:Synapsins / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017470:Receptors, Glutamate; D016704:Synapsins; D016708:Synaptophysin; C569015:Syp protein, mouse; C075222:amyloid beta-protein (1-42); D048051:p38 Mitogen-Activated Protein Kinases