A cellular prion protein-dependent signaling pathway for proinflammatory cytokine- and β-amyloid-induced cofilin-actin rod formation
Date
2014
Authors
Walsh, Keifer P., author
Bamburg, James, advisor
Zabel, Mark, committee member
Tjalkens, Ron, committee member
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Abstract
Stimulus of oxidative stress in neurodegeneration leads to synaptic dysfunction and the eventual loss of neurons in the central nervous system. The actin cytoskeleton of neurons under acute or chronic stress experiences dynamic remodeling due to functional alterations in the actin depolymerizing factor (ADF)/cofilin family of actin-binding proteins. Once oxidized, disulfide cross-linked cofilin incorporates into the formation of tandem arrays of 1:1 cofilin:actin rod-like bundles (rods). Rods sequester cofilin, which is required for synaptic remodeling associated with learning and memory, and interrupt vesicular transport by occluding the neurite within which they form. Different rod-inducing stimuli target distinct neuronal populations within the hippocampus. Rods form rapidly (5-30 min) in >80% of cultured hippocampal neurons which are treated with excitotoxic levels of glutamate or energy depleted (hypoxia/ischemia or mitochondrial inhibitors). In contrast, slow rod formation (50% maximum response in ~6 h) occurs in ~20% of neurons upon exposure to soluble beta-amyoid dimer/trimer (Aβd/t), a physiologically relevant species in Alzheimer disease (AD). Here we show that proinflammatory cytokines (TNFα, IL-1β, IL-6) induce rods at the same rate and in the same subpopulation of hippocampal neurons that respond to Aβd/t. Rod formation by proinflammatory cytokines may link the neuroinflammatory hypothesis for AD with the Aβ hypothesis by providing a common target. Neurons from PrPC-null mice form rods in response to glutamate or antimycin A, but not in response to Aβd/t or proinflammatory cytokines. Prion-dependent rod inducers require the activation of NADPH oxidase (NOX) to generate reactive oxygen species (ROS), but NOX activity is not required for rods induced by glutamate or energy depletion. Aβd/t and TNFα stimulate cofilin dephosphorylation and increased ROS production in a subpopulation of neurites at levels that exceed a minimum threshold to maintain stable rods. Removing inducers or inhibiting NOX activity in cells containing prion-dependent rods causes rod disappearance with a half-life of ~36 minutes. Interestingly, the overexpression of PrPC alone is sufficient to induce rods in >40% of hippocampal neurons, nearly twice the number that respond to Aβd/t or TNFα. This suggests that membrane microdomains containing PrPC recruit the oxidizing machinery necessary to initiate and sustain rod formation. Our hypothesis is supported by the inhibition and reversal of prion-dependent rods by the naturally occurring plant triterpene, ursolic acid (UA), and the pharmacological peptide RAP310. UA and related compounds to RAP310 have been proposed to inhibit changes in the membrane lipid profile that permit LR coalescence. The vast majority of neurodegenerative disorders are considered sporadic in incidence and multifactorial in cause, making treatment at an early stage a significant challenge. If cofilin-actin rods indeed bridge multiple disease initiating mechanisms into a common pathway leading to synapse loss, they provide a valuable target for therapeutic intervention.
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Subject
cofilin
Alzheimer's disease
NADPH oxidase
neurodegeneration
prion
ursolic acid