title: Synaptic transmission block by presynaptic injection of oligomeric amyloid beta.
abstract: Early Alzheimer's disease (AD) pathophysiology is characterized by synaptic changes induced by degradation products of amyloid precursor protein (APP). The exact mechanisms of such modulation are unknown. Here, we report that nanomolar concentrations of intraaxonal oligomeric (o)Abeta42, but not oAbeta40 or extracellular oAbeta42, acutely inhibited synaptic transmission at the squid giant synapse. Further characterization of this phenotype demonstrated that presynaptic calcium currents were unaffected. However, electron microscopy experiments revealed diminished docked synaptic vesicles in oAbeta42-microinjected terminals, without affecting clathrin-coated vesicles. The molecular events of this modulation involved casein kinase 2 and the synaptic vesicle rapid endocytosis pathway. These findings open the possibility of a new therapeutic target aimed at ameliorating synaptic dysfunction in AD.
authors.affiliation: Department of Neurology and Physiology/Pharmacology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.
authors.forename: Herman
authors.initials: H
authors.lastname: Moreno
authors.forename: Eunah
authors.initials: E
authors.lastname: Yu
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pigino
authors.forename: Alejandro I
authors.initials: AI
authors.lastname: Hernandez
authors.forename: Natalia
authors.initials: N
authors.lastname: Kim
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Moreira
authors.forename: Mutsuyuki
authors.initials: M
authors.lastname: Sugimori
authors.forename: Rodolfo R
authors.initials: RR
authors.lastname: Llinás
mesh_terms: D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D047390:Casein Kinase II; D049832:Decapodiformes; D004594:Electrophysiology; D004705:Endocytosis; D008854:Microscopy, Electron; D010446:Peptide Fragments; D017729:Presynaptic Terminals; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D047390:Casein Kinase II