Partial interruption of axonal transport due to microtubule breakage accounts for the formation of periodic varicosities after traumatic axonal injury.
ABSTRACT Due to their viscoelastic nature, white matter axons are susceptible to damage by high strain rates produced during traumatic brain injury (TBI). Indeed, diffuse axonal injury (DAI) is one of the most common features of TBI, characterized by the hallmark pathological profiles of axonal bulbs at disconnected terminal ends of axons and periodic swellings along axons, known as "varicosities." Although transport interruption underlies axonal bulb formation, it is unclear how varicosities arise, with multiple sites accumulating transported materials along one axon. Recently, axonal microtubules have been found to physically break during dynamic stretch injury of cortical axons in vitro. Here, the same in vitro model was used in parallel with histopathological analyses of human brains acquired acutely following TBI to examine the potential role of mechanical microtubule damage in varicosity formation post-trauma. Transmission electron microscopy (TEM) following in vitro stretch injury revealed periodic breaks of individual microtubules along axons that regionally corresponded with undulations in axon morphology. However, typically less than a third of microtubules were broken in any region of an axon. Within hours, these sites of microtubule breaks evolved into periodic swellings. This suggests axonal transport may be halted along one broken microtubule, yet can proceed through the same region via other intact microtubules. Similar axonal undulations and varicosities were observed following TBI in humans, suggesting primary microtubule failure may also be a feature of DAI. These data indicate a novel mechanism of mechanical microtubule damage leading to partial transport interruption and varicosity formation in traumatic axonal injury.
SourceAvailable from: Anton Reiner
Dataset: ijms-16-00758 edited
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ABSTRACT: We have developed a focal blast model of closed-head mild traumatic brain injury (TBI) in mice. As true for individuals that have experienced mild TBI, mice subjected to 50-60 psi blast show motor, visual and emotional deficits, diffuse axonal injury and microglial activation, but no overt neuron loss. Because microglial activation can worsen brain damage after a concussive event and because microglia can be modulated by their cannabinoid type 2 receptors (CB2), we evaluated the effectiveness of the novel CB2 receptor inverse agonist SMM-189 in altering microglial activation and mitigating deficits after mild TBI. In vitro analysis indicated that SMM-189 converted human microglia from the pro-inflammatory M1 phenotype to the pro-healing M2 phenotype. Studies in mice showed that daily administration of SMM-189 for two weeks beginning shortly after blast greatly reduced the motor, visual, and emotional deficits otherwise evident after 50-60 psi blasts, and prevented brain injury that may contribute to these deficits. Our results suggest that treatment with the CB2 inverse agonist SMM-189 after a mild TBI event can reduce its adverse consequences by beneficially modulating microglial activation. These findings recommend further evaluation of CB2 inverse agonists as a novel therapeutic approach for treating mild TBI.International Journal of Molecular Sciences 01/2015; 16(1):758-87. DOI:10.3390/ijms16010758 · 2.46 Impact Factor
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ABSTRACT: Injured axons with distinct morphologies have been found following mild traumatic brain injury (mTBI), although it is currently unclear whether they reflect varied responses to the injury or represent different stages of progressing pathology. This complicates evaluation of therapeutic interventions targeting axonal injury. To address this issue, we assessed axonal injury over time within a well-defined axonal population, while also evaluating mitochondrial permeability transition as a therapeutic target. We utilized mice expressing yellow fluorescent protein (YFP) in cortical neurons which were crossed with mice which lacked Cyclophilin D (CypD), a positive regulator of mitochondrial permeability transition pore opening. Their offspring were subjected to mTBI and the ensuing axonal injury was assessed using YFP expression and amyloid precursor protein (APP) immunohistochemistry, visualized by confocal and electron microscopy. YFP+ axons initially developed a single, APP+, focal swelling (proximal bulb) which progressed to axotomy. Disconnected axonal segments developed either a single bulb (distal bulb) or multiple bulbs (varicosities), which were APP− and whose ultrastructure was consistent with ongoing Wallerian degeneration. CypD knock-out failed to reduce proximal bulb formation but decreased the number of distal bulbs and varicosities, as well as a population of small, APP+, callosal bulbs not associated with YFP+ axons. The observation that YFP+ axons contain several pathological morphologies points to the complexity of traumatic axonal injury. The fact that CypD knock-out reduced some, but not all, subtypes highlights the need to appropriately characterize injured axons when evaluating potential neuroprotective strategies.Acta Neuropathologica 12/2014; 129(2). DOI:10.1007/s00401-014-1376-x · 9.78 Impact Factor