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Author Notes:

E-mail: James.Bamburg@ColoState.edu.

For author contributions and acknowledgments, see the full article.

The authors have declared that no competing interests exist.

The funders except the named authors played no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Subjects:

Research Funding:

Research was supported in part by National Institutes of Health grants NS040371 and AG044812 (JRB), GM103395 (TBK), a Colorado State University Core Infrastructure Grant, and generous donations to the Colorado State University Research Foundation in support of the authors' research.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • CREUTZFELDT-JAKOB-DISEASE
  • CENTRAL-NERVOUS-SYSTEM
  • ALZHEIMERS-DISEASE
  • A-BETA
  • MITOCHONDRIAL DYSFUNCTION
  • SYNAPTIC PLASTICITY
  • NOX ENZYMES
  • NEURODEGENERATIVE DISEASES
  • RANBP9-COFILIN PATHWAY
  • Neurons
  • Cytokines
  • Adenoviruses
  • Alzheimer disease
  • Neurites
  • Glutamate
  • Oxidation
  • Cognitive impairment

Amyloid-beta and Proinflammatory Cytokines Utilize a Prion Protein-Dependent Pathway to Activate NADPH Oxidase and Induce Cofilin-Actin Rods in Hippocampal Neurons

Journal Title:

PLoS ONE

Volume:

Volume 9, Number 4

Publisher:

, Pages e95995-e95995

Type of Work:

Article | Final Publisher PDF

Abstract:

Neurites of neurons under acute or chronic stress form bundles of filaments (rods) containing 1:1 cofilin:actin, which impair transport and synaptic function. Rods contain disulfide cross-linked cofilin and are induced by treatments resulting in oxidative stress. Rods form rapidly (5-30 min) in >80% of cultured hippocampal or cortical neurons treated with excitotoxic levels of glutamate or energy depleted (hypoxia/ischemia or mitochondrial inhibitors). In contrast, slow rod formation (50% of maximum response in ∼6 h) occurs in a subpopulation (∼20%) of hippocampal neurons upon exposure to soluble human amyloid-β dimer/trimer (Aβd/t) at subnanomolar concentrations. Here we show that proinflammatory cytokines (TNFα, IL-1β, IL-6) also induce rods at the same rate and within the same neuronal population as Abd/t. Neurons from prion (PrPC)-null mice form rods in response to glutamate or antimycin A, but not in response to proinflammatory cytokines or Aβd/t. Two pathways inducing rod formation were confirmed by demonstrating that NADPH-oxidase (NOX) activity is required for prion-dependent rod formation, but not for rods induced by glutamate or energy depletion. Surprisingly, overexpression of PrPC is by itself sufficient to induce rods in over 40% of hippocampal neurons through the NOX-dependent pathway. Persistence of PrPC-dependent rods requires the continuous activity of NOX. Removing inducers or inhibiting NOX activity in cells containing PrPC-dependent rods causes rod disappearance with a half-life of about 36 min. Cofilin-actin rods provide a mechanism for synapse loss bridging the amyloid and cytokine hypotheses for Alzheimer disease, and may explain how functionally diverse Ab -binding membrane proteins induce synaptic dysfunction.

Copyright information:

© 2014 Walsh et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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