β-Amyloid precursor protein (βAPP) as a marker for axonal injury after head injury

Gentleman, Stephen M.; Nash, Michael J.; Sweeting, Christopher J.; Graham, David I.; Roberts, Gareth W.

doi:10.1016/0304-3940(93)90398-5

Cited by 524 publications

(339 citation statements)

References 19 publications

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“…␤-APP rapidly accumulates at sites of injury, stains damaged axons within 2 hours after injury, and remains detectable in axons and bulbs for more than 2 weeks. 9,17,20 In this study, all fatal malaria cases died within 2 weeks of admission to hospital. Therefore all damaged axons should remain visibly labeled using this method.…”

Section: Discussionmentioning

confidence: 80%

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Axonal Injury in Cerebral Malaria

Medana¹,

Day²,

Hien³

et al. 2002

The American Journal of Pathology

157

130

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Impairment of consciousness and other signs of cerebral dysfunction are common complications of severe Plasmodium falciparum malaria. Although the majority of patients make a complete recovery a significant minority, particularly children, have sequelae. The pathological process by which P. falciparum malaria induces severe but usually reversible neurological complications has not been elucidated. Impairment of transport within nerve fibers could induce neurological dysfunction and may have the potential either to resolve or to progress to irreversible damage. ␤-amyloid precursor protein (␤-APP) immunocytochemistry, quantified using digital image analysis, was used to detect defects in axonal transport in brain sections from 54 Vietnamese cases with P. falciparum malaria. The frequency and extent of ␤-APP staining were more severe in patients with cerebral malaria than in those with no clinical cerebral involvement. ␤-APP staining was often associated with hemorrhages and areas of demyelination, suggesting that multiple processes may be involved in neuronal injury. The age of focal axonal damage, as determined by the extent of the associated microglial response, varied considerably within tissue sections from individual patients. These findings suggest that axons are vulnerable to a broad range of cerebral insults that occur during P. falciparum malaria infection. Disruption in axonal transport may represent a final common pathway leading to neurological dysfunction in cerebral malaria. Cerebral malaria (CM) is a diffuse, potentially reversible, encephalopathy, caused by infection with the protozoan parasite Plasmodium falciparum. CM presents clinically with convulsions and coma, and carries 15 to 20% mortality. The malaria parasite invades and develops within erythrocytes that sequester in the cerebral microvasculature and other vital organs by adhesion to specific endothelial receptors. 1,2 The pathophysiological consequences of severe malaria infection have not been satisfactorily resolved. In particular it is not known how parasitized red blood cells, which remain within the vascular space, influence parenchymal brain function to induce coma and death. Histopathological studies reveal a variety of neurological abnormalities including chromatolysis, neuronophagia, and decreased glial cell numbers. [2][3][4][5]

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Section: Discussionmentioning

confidence: 80%

“…␤-amyloid precursor protein (␤-APP) is a protein that is normally transported along the axon, and accumulates at the sites of AI. 9 Positive ␤-APP immunostaining of axons may identify axons with reversible structural and biochemical changes. 10 Axonal damage may occur gradually, leaving a window for therapeutic intervention during the early stages.…”

mentioning

confidence: 99%

Axonal Injury in Cerebral Malaria

Medana¹,

Day²,

Hien³

et al. 2002

The American Journal of Pathology

157

130

View full text Add to dashboard Cite

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“…Primary axotomy can occur with severe insults, leading to disconnection of axon processes and to axonal swelling. Secondary axotomy can result in an inhibition of axoplasmic flow as evidenced by ß-APP accumulation after human (Gentleman et al, 1993;Sheriff et al, 1994) and experimental TBI (Bramlett et al, 1997b;Pierce et al, 1996) (Fig. 1B).…”

Section: White Matter Vulnerabilitymentioning

confidence: 98%

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Bramlett

Dietrich

2004

J Cereb Blood Flow Metab

567

358

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Summary: Current knowledge regarding the pathophysiology of cerebral ischemia and brain trauma indicates that similar mechanisms contribute to loss of cellular integrity and tissue destruction. Mechanisms of cell damage include excitotoxicity, oxidative stress, free radical production, apoptosis and inflammation. Genetic and gender factors have also been shown to be important mediators of pathomechanisms present in both injury settings. However, the fact that these injuries arise from different types of primary insults leads to diverse cellular vulnerability patterns as well as a spectrum of injury processes. Blunt head trauma produces shear forces that result in primary membrane damage to neuronal cell bodies, white matter structures and vascular beds as well as secondary injury mechanisms. Severe cerebral ischemic insults lead to metabolic stress, ionic perturbations, and a complex cascade of biochemical and molecular events ultimately causing neuronal death. Similarities in the pathogenesis of these cerebral injuries may indicate that therapeutic strategies protective following ischemia may also be beneficial after trauma. This review summarizes and contrasts injury mechanisms after ischemia and trauma and discusses neuroprotective strategies that target both types of injuries.

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“…3,6,11 More modern approaches using antibodies to transported proteins, Research, NICHD, NIH such as amyloid precursor protein (APP), however, have become the gold standard in evaluating the occurrence of DAI in both the routine neuropathologic and forensic settings as well as animal investigations. 10,[12][13][14][15][16][17][18] Specifically, as APP moves down the axonal cylinder via anterograde axonal transport, any focal disruption/ perturbation of the axon and its transport kinetics can lead to local swelling that then can be easily identified by the pooling of APP. 19,20 Through the use of these antibodies in both neuropathologic and forensic settings, the overall occurrence and distribution of traumatically induced axonal change has become even more apparent and has extended many of those observations initially made via the use of more traditional histological approaches (Fig.…”

Section: Histopathological Identification Of Daimentioning

confidence: 99%

Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

174

146

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Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled.

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β-Amyloid precursor protein (βAPP) as a marker for axonal injury after head injury

Cited by 524 publications

References 19 publications

Axonal Injury in Cerebral Malaria

Axonal Injury in Cerebral Malaria

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Therapy Development for Diffuse Axonal Injury

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