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Amyloid-β-induced action potential desynchronization and degradation of hippocampal gamma oscillations is prevented by interference with peptide conformation change and aggregation.

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... Full description

Journal Title: The Journal of neuroscience : the official journal of the Society for Neuroscience August 20, 2014, Vol.34(34), pp.11416-11425
Main Author: Kurudenkandy, Firoz Roshan
Other Authors: Zilberter, Misha , Biverstål, Henrik , Presto, Jenny , Honcharenko, Dmytro , Strömberg, Roger , Johansson, Jan , Winblad, Bengt , Fisahn, André
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1529-2401 ; DOI: 10.1523/JNEUROSCI.1195-14.2014
Link: http://search.proquest.com/docview/1555621460/?pq-origsite=primo
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title: Amyloid-β-induced action potential desynchronization and degradation of hippocampal gamma oscillations is prevented by interference with peptide conformation change and aggregation.
format: Article
creator:
  • Kurudenkandy, Firoz Roshan
  • Zilberter, Misha
  • Biverstål, Henrik
  • Presto, Jenny
  • Honcharenko, Dmytro
  • Strömberg, Roger
  • Johansson, Jan
  • Winblad, Bengt
  • Fisahn, André
subjects:
  • Action Potentials–Drug Effects
  • Amyloid Beta-Peptides–Chemistry
  • Animals–Metabolism
  • Biological Clocks–Pharmacology
  • Ca3 Region, Hippocampal–Ultrastructure
  • Excitatory Amino Acid Agonists–Drug Effects
  • Female–Cytology
  • In Vitro Techniques–Physiology
  • Kainic Acid–Pharmacology
  • Male–Pharmacology
  • Mice–Drug Effects
  • Mice, Inbred C57bl–Physiology
  • Nerve Net–Drug Effects
  • Neurons–Chemistry
  • Patch-Clamp Techniques–Metabolism
  • Peptide Fragments–Pharmacology
  • Protein Aggregates–Ultrastructure
  • Protein Conformation–Drug Effects
  • Spectrum Analysis–Drug Effects
  • Synaptic Transmission
ispartof: The Journal of neuroscience : the official journal of the Society for Neuroscience, August 20, 2014, Vol.34(34), pp.11416-11425
description: 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.
language: eng
source:
identifier: E-ISSN: 1529-2401 ; DOI: 10.1523/JNEUROSCI.1195-14.2014
fulltext: fulltext
issn:
  • 15292401
  • 1529-2401
url: Link


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titleAmyloid-β-induced action potential desynchronization and degradation of hippocampal gamma oscillations is prevented by interference with peptide conformation change and aggregation.
creatorKurudenkandy, Firoz Roshan ; Zilberter, Misha ; Biverstål, Henrik ; Presto, Jenny ; Honcharenko, Dmytro ; Strömberg, Roger ; Johansson, Jan ; Winblad, Bengt ; Fisahn, André
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identifierE-ISSN: 1529-2401 ; DOI: 10.1523/JNEUROSCI.1195-14.2014
subjectAction Potentials–Drug Effects ; Amyloid Beta-Peptides–Chemistry ; Animals–Metabolism ; Biological Clocks–Pharmacology ; Ca3 Region, Hippocampal–Ultrastructure ; Excitatory Amino Acid Agonists–Drug Effects ; Female–Cytology ; In Vitro Techniques–Physiology ; Kainic Acid–Pharmacology ; Male–Pharmacology ; Mice–Drug Effects ; Mice, Inbred C57bl–Physiology ; Nerve Net–Drug Effects ; Neurons–Chemistry ; Patch-Clamp Techniques–Metabolism ; Peptide Fragments–Pharmacology ; Protein Aggregates–Ultrastructure ; Protein Conformation–Drug Effects ; Spectrum Analysis–Drug Effects ; Synaptic Transmission
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descriptionThe 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.
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titleAmyloid-β-induced action potential desynchronization and degradation of hippocampal gamma oscillations is prevented by interference with peptide conformation change and aggregation.
authorKurudenkandy, Firoz Roshan ; Zilberter, Misha ; Biverstål, Henrik ; Presto, Jenny ; Honcharenko, Dmytro ; Strömberg, Roger ; Johansson, Jan ; Winblad, Bengt ; Fisahn, André
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