Abstract
A persistent inflammatory and oxidative stress is a hallmark of most chronic CNS pathologies (Alzheimer's (ALS)) as well as the aging CNS orchestrated by the proinflammatory cytokines tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β). Loss of the integrity and plasticity of neuronal morphology and connectivity comprises an early step in neuronal degeneration and ultimate decline of cognitive function. We examined in vitro whether TNFα or IL-1β impaired morphology and motility of growth cones in spinal cord neuron cultures. TNFα and IL-1β paralyzed growth cone motility and induced growth cone collapse in a dose-dependent manner reflected by complete attenuation of neurite outgrowth. Scavenging reactive oxygen species (ROS) or inhibiting NADPH oxidase activity rescued loss of neuronal motility and morphology. TNFα and IL-1β provoked rapid, NOX-mediated generation of ROS in advancing growth cones, which preceded paralysis of motility and collapse of morphology. Increases in ROS intermediates were accompanied by an aberrant, nonproductive reorganization of actin filaments. These findings suggest that NADPH oxidase serves as a pivotal source of oxidative stress in neurons and together with disruption of actin filament reorganization contributes to the progressive degeneration of neuronal morphology in the diseased or aging CNS.
Highlights
A spreading inflammatory reaction accompanied by oxidative stress is prevalent in most chronic CNS diseases and acute CNS trauma as well as in the aging CNS [1,2,3]
Rho GTPases harbor a dual role in cytokine signaling as regulators of both NADPH oxidase (NOX) assembly and the reorganization of actin filament structures [21,22,23]. In light of these reports, we examined whether reactive oxygen species (ROS) intermediates generated by NOX activities in neuronal growth cones are implicated in mediating the neurotoxic effects of tumor necrosis factor α (TNFα) or IL1β on neurite outgrowth
We examined whether TNFα or IL-1β has the potency to alter motility of neuronal growth cones, an actin-cytoskeleton driven mechanism
Summary
A spreading inflammatory reaction accompanied by oxidative stress is prevalent in most chronic CNS diseases and acute CNS trauma as well as in the aging CNS [1,2,3]. The intricate pattern of neuronal connectivity innate to cognitive function rests as much on the integrity and stability of the axonal and dendritic architecture as on the plasticity of motile structures to maintain, form, or regenerate connections, which is intimately linked to the dynamic reorganization of the actin cytoskeleton [10, 11]. ROS intermediates greatly affect both the dynamics and organization of actin filaments during oxidative stress of physiological redox signaling [12, 13]. TNFα paralyzed actin filament reorganization in neuroblastoma cells due to oxidative damage, whereas physiological levels of ROS intermediates seem to be necessary for proper growth cone motility [14, 15]. The members of the NADPH oxidase (NOX) family (NOX1– 5, DUOX1/2), defined by the large membrane flavoprotein gp91phox of the phagocyte NAPDH oxidase (NOX2), are ubiquitously expressed in all cell types and have emerged as principal ROS sources both in cellular signaling and disease
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