%0 Journal Article
%T Amyloid-¦Â and Proinflammatory Cytokines Utilize a Prion Protein-Dependent Pathway to Activate NADPH Oxidase and Induce Cofilin-Actin Rods in Hippocampal Neurons
%A Keifer P. Walsh
%A Laurie S. Minamide
%A Sarah J. Kane
%A Alisa E. Shaw
%A David R. Brown
%A Bruce Pulford
%A Mark D. Zabel
%A J. David Lambeth
%A Thomas B. Kuhn
%A James R. Bamburg
%J PLOS ONE
%D 2014
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0095995
%X 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¨C30 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-¦Â dimer/trimer (A¦Âd/t) at subnanomolar concentrations. Here we show that proinflammatory cytokines (TNF¦Á, IL-1¦Â, IL-6) also induce rods at the same rate and within the same neuronal population as A¦Âd/t. Neurons from prion (PrPC)-null mice form rods in response to glutamate or antimycin A, but not in response to proinflammatory cytokines or A¦Âd/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 A¦Â-binding membrane proteins induce synaptic dysfunction.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0095995