Academic literature on the topic 'Amyloid precursor protein; traumatic brain injury; sAPPα'

Objective:To determine whether postconcussion syndrome (PCS) due to repetitive concussive traumatic brain injury (rcTBI) is associated with CSF biomarker evidence of astroglial activation, amyloid deposition, and blood–brain barrier (BBB) impairment.Methods:A total of 47 participants (28 professional athletes with PCS and 19 controls) were assessed with lumbar puncture (median 1.5 years, range 0.25–12 years after last concussion), standard MRI of the brain, and Rivermead Post-Concussion Symptoms Questionnaire (RPQ). The main outcome measures were CSF concentrations of astroglial activation markers (glial fibrillary acidic protein [GFAP] and YKL-40), markers reflecting amyloid precursor protein metabolism (Aβ38, Aβ40, Aβ42, sAPPα, and sAPPβ), and BBB function (CSF:serum albumin ratio).Results:Nine of the 28 athletes returned to play within a year, while 19 had persistent PCS >1 year. Athletes with PCS >1 year had higher RPQ scores and number of concussions than athletes with PCS <1 year. Median concentrations of GFAP and YKL-40 were higher in athletes with PCS >1 year compared with controls, although with an overlap between the groups. YKL-40 correlated with RPQ score and the lifetime number of concussions. Athletes with rcTBI had lower concentrations of Aβ40 and Aβ42 than controls. The CSF:serum albumin ratio was unaltered.Conclusions:This study suggests that PCS may be associated with biomarker evidence of astroglial activation and β-amyloid (Aβ) dysmetabolism in the brain. There was no clear evidence of Aβ deposition as Aβ40 and Aβ42 were reduced in parallel. The CSF:serum albumin ratio was unaltered, suggesting that the BBB is largely intact in PCS.

Abstract Context.—Inflicted traumatic brain injury of infants and young children results in a complex array of autopsy findings. In many cases, immunostains for β-amyloid precursor protein are used to detect axonal injury. Interpretation of the gross, microscopic, and immunostaining results requires the integration of the many facets of the individual case. Objective.—In this article we review the gross and microscopic findings associated with inflicted traumatic brain injury. The application and interpretation of β-amyloid precursor protein immunostains are discussed and photomicrographs are used to illustrate immunostaining patterns. Data Sources.—The pertinent literature is integrated into a review of the subject. Conclusions.—Inflicted traumatic brain injury often results in subdural, subarachnoid, retinal, and optic nerve sheath hemorrhage. These findings must be interpreted within the entire context of the case. β-Amyloid precursor protein immunostains may be helpful in illustrating the traumatic nature of the injuries in some cases.

Voltage-gated sodium channel beta 2 (Nav2.2 or Navβ2, coded by SCN2B mRNA), a gene involved in maintaining normal physiological functions of the prefrontal cortex and hippocampus, might be associated with prefrontal cortex aging and memory decline. This study investigated the effects of Navβ2 in amyloid-β 1-42- (Aβ1-42-) induced neural injury model and the potential underlying molecular mechanism. The results showed that Navβ2 knockdown restored neuronal viability of Aβ1-42-induced injury in neurons; increased the contents of brain-derived neurotrophic factor (BDNF), enzyme neprilysin (NEP) protein, and NEP enzyme activity; and effectively altered the proportions of the amyloid precursor protein (APP) metabolites including Aβ42, sAPPα, and sAPPβ, thus ameliorating cognitive dysfunction. This may be achieved through regulating NEP transcription and APP metabolism, accelerating Aβ degradation, alleviating neuronal impairment, and regulating BDNF-related signal pathways to repair neuronal synaptic efficiency. This study provides novel evidence indicating that Navβ2 plays crucial roles in the repair of neuronal injury induced by Aβ1-42 both in vivo and in vitro.

The current work reviews the concept, pathological mechanism, and process of diagnosing of DAI. The pathological mechanism underlying DAI is complicated, including axonal breakage caused by axonal retraction balls, discontinued protein transport along the axonal axis, calcium influx, and calpain-mediated hydrolysis of structural protein, degradation of axonal cytoskeleton network, the changes of transport proteins such as amyloid precursor protein, and changes of glia cells. Based on the above pathological mechanism, the diagnosis of DAI is usually made using methods such as CT, traditional and new MRI, biochemical markers, and neuropsychological assessment. This review provides a basis in literature for further investigation and discusses the pathological mechanism. It may also facilitate improvement of the accuracy of diagnosis for DAI, which may come to play a critical role in breaking through the bottleneck of the clinical treatment of DAI and improving the survival and quality of life of patients through clear understanding of pathological mechanisms and accurate diagnosis.

Traumatic brain injury (TBI) is a leading cause of disability worldwide. Annually, 150 to 200/1,000,000 people become disabled as a result of brain trauma. Axonal degeneration is a critical, early event following TBI of all severities but whether axon degeneration is a driver of TBI remains unclear. Molecular pathways underlying the pathology of TBI have not been defined and there is no efficacious treatment for TBI. Despite this significant societal impact, surprisingly little is known about the molecular mechanisms that actively drive axon degeneration in any context and particularly following TBI. Although severe brain injury may cause immediate disruption of axons (primary axotomy), it is now recognized that the most frequent form of traumatic axonal injury (TAI) is mediated by a cascade of events that ultimately result in secondary axonal disconnection (secondary axotomy) within hours to days. Proposed mechanisms include immediate post-traumatic cytoskeletal destabilization as a direct result of mechanical breakage of microtubules, as well as catastrophic local calcium dysregulation resulting in microtubule depolymerization, impaired axonal transport, unmitigated accumulation of cargoes, local axonal swelling, and finally disconnection. The portion of the axon that is distal to the axotomy site remains initially morphologically intact. However, it undergoes sudden rapid fragmentation along its full distal length ~72 h after the original axotomy, a process termed Wallerian degeneration. Remarkably, mice mutant for the Wallerian degeneration slow (Wlds) protein exhibit ~tenfold (for 2–3 weeks) suppressed Wallerian degeneration. Yet, pharmacological replication of the Wlds mechanism has proven difficult. Further, no one has studied whether Wlds protects from TAI. Lastly, owing to Wlds presumed gain-of-function and its absence in wild-type animals, direct evidence in support of a putative endogenous axon death signaling pathway is lacking, which is critical to identify original treatment targets and the development of viable therapeutic approaches. Novel insight into the pathophysiology of Wallerian degeneration was gained by the discovery that mutant Drosophila flies lacking dSarm (sterile a/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously recapitulated the Wlds phenotype. The pro-degenerative function of the dSarm gene (and its mouse homolog Sarm1) is widespread in mammals as shown by in vitro protection of superior cervical ganglion, dorsal root ganglion, and cortical neuron axons, as well as remarkable in-vivo long-term survival (>2 weeks) of transected sciatic mouse Sarm1 null axons. Although the molecular mechanism of function remains to be clarified, its discovery provides direct evidence that Sarm1 is the first endogenous gene required for Wallerian degeneration, driving a highly conserved genetic axon death program. The central goals of this thesis were to determine (1) whether post-traumatic axonal integrity is preserved in mice lacking Sarm1, and (2) whether loss of Sarm1 is associated with improved functional outcome after TBI. I show that mice lacking the mouse Toll receptor adaptor Sarm1 gene demonstrate multiple improved TBI-associated phenotypes after injury in a closed-head mild TBI model. Sarm1-/- mice developed fewer beta amyloid precursor protein (βAPP) aggregates in axons of the corpus callosum after TBI as compared to Sarm1+/+ mice. Furthermore, mice lacking Sarm1 had reduced plasma concentrations of the phosphorylated axonal neurofilament subunit H, indicating that axonal integrity is maintained after TBI. Strikingly, whereas wild type mice exhibited a number of behavioral deficits after TBI, I observed a strong, early preservation of neurological function in Sarm1-/- animals. Finally, using in vivo proton magnetic resonance spectroscopy, I found tissue signatures consistent with substantially preserved neuronal energy metabolism in Sarm1-/- mice compared to controls immediately following TBI. My results indicate that the Sarm1-mediated prodegenerative pathway promotes pathogenesis in TBI and suggest that anti-Sarm1 therapeutics are a viable approach for preserving neurological function after TBI.

The amyloid precursor protein (APP) is known to increase following traumatic brain injury (TBI). It has been hypothesised that this increase in APP may be deleterious to outcome due to the production of neurotoxic Aβ. Conversely, this upregulation may be beneficial as cleavage of APP via the alternative non-amyloidogenic pathway produces the soluble alpha form of APP (sAPPα), which is known to have many neuroprotective and neurotrophic functions. Indeed a previous study showed that treatment with sAPPα following a diffuse injury in rats reduced apoptotic cell death and axonal injury which corresponded with an improvement in motor outcome. However, it is not yet known whether endogenous APP plays a similar beneficial role following TBI, or which specific region within sAPPα conferred this protective activity. In order to investigate this the effect of post-traumatic administration of various regions within sAPPα was examined following severe-impact acceleration TBI in Sprague Dawley rats. Furthermore the outcome of male C57BL6j x 129sv APP-/- mice was compared to that of APP+/+ mice following two types of traumatic brain injury; a diffuse lesion caused by a weight drop model and a focal lesion induced by a controlled cortical impact (CCI) injury. Knockout of APP was found to worsen outcome following both a mild diffuse and moderate focal injury, with an exacerbation of motor and cognitive deficits associated with an increase in neuronal injury and an impaired reparative response. These deficits could be rescued with treatment with sAPPα, suggesting that it was lack of this APP metabolite which caused the increase in vulnerability of APP-/- mice. Furthermore initial investigations in Sprague Dawley rats found that only the domains of sAPPα that contained heparin binding sites were able to improve functional outcome and decrease axonal injury following diffuse TBI. This suggested that the neuroprotective activity of sAPPα related to its ability to bind to heparin sulphate proteoglycans. Indeed a preliminary investigation found that the peptide APP96-110, which encompassess one of the heparin binding sites within sAPPα, was sufficient to reduce functional deficits and neuronal injury in APP-/- mice. These results demonstrate that the upregulation of APP seen following TBI is a protective response, with the benefits of sAPPα outweighing any negative effects of other APP metabolites like Aβ. The neuroprotective properties of sAPPα, may relate to its heparin binding sites, with one of these regions, APP96-110, warranting further investigation as a putative neuroprotective agent following TBI.
Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2011

Appendum pasted into front end-papers.
Bibliography: leaves xiii-xliii.
xi, 195, xliii leaves : ill. (chiefly col.) ; 30 cm.
Traumatic brain injury (TBI) effects neuronal cell bodies (NCBs), axons and dendrites in a complex fashion, producing a spectrum of damage dependent on the initial injury and secondary effects. Accumulation of amyloid precursor (APP) in NSBs and axons is a feature of TBI. This accumulation may be due to impairment of the axonal transport of APP and/or upregulation of APP mRNA synthesis. This thesis hypothesizes that mechanical deformation, which is not severe enough to cause immediate cell death, results in increased APP mRNA and antigen expression as an acute phase response to injury.
Thesis (Ph.D.)--University of Adelaide, Dept. of Pathology, 1999

In this study, changes in viscoelastic material properties of brain tissue due to traumatic axonal injury (TAI) were investigated. The impact acceleration model was used to generate diffuse axonal injury in rat brain. TAI in the corticospinal (CSpT) tract in the brain stem was quantified using amyloid precursor protein immunostaining. Material properties along the CSpT were determined using an indentation technique. The results showed that the number of injured axons at the pyramidal decussation (PDx) was approximated 10 times higher than in the ponto-medullary junction (PmJ). The instantaneous elastic response was reduced approximately 70% at PDx compared to 40% at PmJ and the relaxation was uniformly reduced approximately 30%, which were attributed to the effect of injury on tissue properties. Application of a visco-elastic-plastic model that changes due to TAI can significantly alter the results of computational models of brain injury.