Amyloid-β and proinflammatory cytokines utilize a prion protein-dependent pathway to activate NADPH oxidase and induce cofilin-actin rods in hippocampal neurons

Keifer P Walsh, Laurie S Minamide, Sarah J Kane, Alisa E Shaw, David R Brown, Bruce Pulford, Mark D Zabel, J David Lambeth, Thomas B Kuhn, James R Bamburg

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

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 Aβd/t. Neurons from prion (PrP(C))-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 PrP(C) is by itself sufficient to induce rods in over 40% of hippocampal neurons through the NOX-dependent pathway. Persistence of PrP(C)-dependent rods requires the continuous activity of NOX. Removing inducers or inhibiting NOX activity in cells containing PrP(C)-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 Aβ-binding membrane proteins induce synaptic dysfunction.

Original languageEnglish
Pages (from-to)e95995
JournalPLoS ONE
Volume9
Issue number4
DOIs
Publication statusPublished - 23 Apr 2014

Keywords

  • Actin Depolymerizing Factors
  • Actins
  • Amyloid beta-Peptides
  • Animals
  • Cells, Cultured
  • Dactinomycin
  • Female
  • Gene Expression Regulation
  • Glutamic Acid
  • Hippocampus
  • Humans
  • Inflammation
  • Mice
  • NADPH Oxidase
  • Neurites
  • PrPC Proteins
  • Rats
  • Signal Transduction
  • Synaptic Transmission
  • Tumor Necrosis Factor-alpha

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