Traumatically Induced Axotomy Adjacent to the Soma Does Not Result in Acute Neuronal Death

Abstract

Traumatic axonal injury (TAI), a consequence of traumatic brain injury (TBI), results from progressive pathologic processes initiated at the time of injury. Studies attempting to characterize the pathology associated with TAI have not succeeded in following damaged and/or disconnected axonal segments back to their individual neuronal somata to determine their fate. To address this issue, 71 adult male Sprague Dawley rats were subjected to moderate central fluid percussion injury and killed between 30 min and 7 d after injury. Antibodies to the C terminus of ␤-amyloid precursor protein (APP) identified TAI in continuity with individual neuronal somata in the mediodorsal neocortex, the hilus of the dentate gyrus, and the dorsolateral thalamus. These somata were followed with immunocytochemical markers of neuronal injury targeting phosphorylated 200 kDa neurofilaments (RMO-24), altered protein translation (phosphorylated eukaryotic translation initiation factor 2␣), and cell death [terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)], with parallel electron microscopic (EM) assessment. Despite the finding of TAI within 20-50 m of the soma, no evidence of cell death, long associated with proximal axotomy, was seen via TUNEL or routine light microscopy/electron microscopy. Rather, there was rapid onset (Ͻ6 hr after injury) subcellular change associated with impaired protein synthesis identified by EM, immunocytochemical, and Western blot analyses. When followed 7 d after injury, these abnormalities did not reveal dramatic progression. Rather, some somata showed evidence of potential reorganization and repair. This study demonstrates a novel somatic response to TAI in the perisomatic domain and also provides insight into the multifaceted pathology associated with TBI.

Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons

“…APP-labeled segments became longer, and in many cases ended in larger spheroids or club-like swellings and were detected up to 24 hrs post-injury. This type of pathomorphological changes and the rapid increase in swelling diameter most likely represent impairment of axonal integrity and eventual axonal disconnection in the developing white matter, and were also implicated in axotomy in adults (Stone et al, 2000;Singleton et al, 2002;Buki and Povlishock, 2006;Kelley et al, 2006). It is further supported by our ultrastructural analysis, which revealed advanced degeneration of many axonal profiles in the form of axolemmal disintegration.…”

“…It is further supported by our ultrastructural analysis, which revealed advanced degeneration of many axonal profiles in the form of axolemmal disintegration. In the thalamus of adult rats early perisomatic axonal swellings were also detected at the junction between the proximal unmyelinated and myelinated segments, which was implemented as a point of biomechanical vulnerability (Singleton et al, 2002, Kelley, 2006. In contrast, after mild injury in infant mice perisomatic axonal injury in the cortex and thalamus was not detected.…”

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

“…Axonal damage was among the first identified features of LOAD pathology [34] and subsequent studies using axotomy models established a link between the loss of overall neuronal polarity and perisomatic axonal injury [222][223][224][225]. We propose that an interplay between predisposing factors such as axon injury or reduced mitochondrial function amplify axonal changes due to tau misprocessing, neuronal dedifferentiation and Aβ generation [226][227][228][229][230].…”

Relationship between Flow-Metabolism Uncoupling and Evolving Axonal Injury after Experimental Traumatic Brain Injury

“…The existence of a threshold for the accumulation of ␤-APP may not be surprising because at least in gray matter, the degree of ischemia-induced ␤-APP expression at 24 hours in the gerbil was correlated with the length of the preceding ischemic period (Tomimoto et al, 1994), whereas reperfusion until 24 hours in the rat resulted in a remarkable reduction in axonal ␤-APP staining compared to permanent ischemia (Valeriani et al, 2000). Similarly, it may not be purely coincidental that the acute time-point blood-flow threshold associated with the progression of axonal damage corresponds roughly to the threshold of 55 mL min −1 100 g −1 for the suppression of protein synthesis in the gray matter of ischemic brain (Mies et al, 1991), because protein translation is inhibited within 4 to 24 hours of fluid percussion injury in neuronal perikarya of ␤-APP-positive axons (Singleton et al, 2002).…”

“…Because of the progressive nature of the axonal response to injury, it is important to determine the precise mechanism(s) through which secondary axotomy occurs in order that appropriate therapeutic strategies may be developed. Axonal damage can occur as a direct consequence of local ischemic (Pantoni et al, 1996;Yam et al, 1998) or hypoxic conditions (Waxman et al, 1992) and is not always associated with cell body pathology and progression to cell death after trauma (Singleton et al, 2002). Although TBI may not necessarily result in ischemic conditions that are classically associated with energy failure, flow-metabolism uncoupling may render the axons vulnerable to secondary insults.…”