title: Amyloid-β-induced action potential desynchronization and degradation of hippocampal gamma oscillations is prevented by interference with peptide conformation change and aggregation.
abstract: The amyloid-β hypothesis of Alzheimer's Disease (AD) focuses on accumulation of amyloid-β peptide (Aβ) as the main culprit for the myriad physiological changes seen during development and progression of AD including desynchronization of neuronal action potentials, consequent development of aberrant brain rhythms relevant for cognition, and final emergence of cognitive deficits. The aim of this study was to elucidate the cellular and synaptic mechanisms underlying the Aβ-induced degradation of gamma oscillations in AD, to identify aggregation state(s) of Aβ that mediate the peptides neurotoxicity, and to test ways to prevent the neurotoxic Aβ effect. We show that Aβ(1-42) in physiological concentrations acutely degrades mouse hippocampal gamma oscillations in a concentration- and time-dependent manner. The underlying cause is an Aβ-induced desynchronization of action potential generation in pyramidal cells and a shift of the excitatory/inhibitory equilibrium in the hippocampal network. Using purified preparations containing different aggregation states of Aβ, as well as a designed ligand and a BRICHOS chaperone domain, we provide evidence that the severity of Aβ neurotoxicity increases with increasing concentration of fibrillar over monomeric Aβ forms, and that Aβ-induced degradation of gamma oscillations and excitatory/inhibitory equilibrium is prevented by compounds that interfere with Aβ aggregation. Our study provides correlative evidence for a link between Aβ-induced effects on synaptic currents and AD-relevant neuronal network oscillations, identifies the responsible aggregation state of Aβ and proofs that strategies preventing peptide aggregation are able to prevent the deleterious action of Aβ on the excitatory/inhibitory equilibrium and on the gamma rhythm.
authors.affiliation: Neuronal Oscillations Laboratory, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, and.
authors.forename: Firoz Roshan
authors.initials: FR
authors.lastname: Kurudenkandy
authors.affiliation: Neuronal Oscillations Laboratory, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, and.
authors.forename: Misha
authors.initials: M
authors.lastname: Zilberter
authors.affiliation: Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, and.
authors.forename: Henrik
authors.initials: H
authors.lastname: Biverstål
authors.affiliation: Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, and.
authors.forename: Jenny
authors.initials: J
authors.lastname: Presto
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Honcharenko
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Roger
authors.initials: R
authors.lastname: Strömberg
authors.affiliation: Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, and Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, 75123 Uppsala, Sweden, and Institute of Mathematics and Natural Sciences, Tallinn University, 10120 Tallinn, Estonia.
authors.forename: Jan
authors.initials: J
authors.lastname: Johansson
authors.affiliation: Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, and.
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.affiliation: Neuronal Oscillations Laboratory, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, and andre.fisahn@ki.se.
authors.forename: André
authors.initials: A
authors.lastname: Fisahn
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000648:ultrastructure; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects*; D056654:CA3 Region, Hippocampal / Q000166:cytology* / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000648:ultrastructure; D066329:Protein Aggregates / Q000187:drug effects*; D011487:Protein Conformation / Q000187:drug effects; D013057:Spectrum Analysis; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D018690:Excitatory Amino Acid Agonists; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D007608:Kainic Acid
keywords: Alzheimer's disease; BRICHOS domain; amyloid-β peptide; gamma oscillations; hippocampus; neuronal synchronization