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Aging and disease    2016, Vol. 7 Issue (2) : 163-179     DOI: 10.14336/AD.2015.0907
Review Article |
The Neuroprotective Properties of the Amyloid Precursor Protein Following Traumatic Brain Injury
Plummer Stephanie1, Van den Heuvel Corinna1, Thornton Emma1, Corrigan Frances1, Cappai Roberto2,*
1Adelaide Centre for Neuroscience Research, the University of Adelaide, South Australia, Australia
2Department of Pathology, the University of Melbourne, Victoria, Australia
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Abstract  

Despite the significant health and economic burden that traumatic brain injury (TBI) places on society, the development of successful therapeutic agents have to date not translated into efficacious therapies in human clinical trials. Injury to the brain is ongoing after TBI, through a complex cascade of primary and secondary injury events, providing a valuable window of opportunity to help limit and prevent some of the severe consequences with a timely treatment. Of note, it has been suggested that novel treatments for TBI should be multifactorial in nature, mimicking the body’s own endogenous repair response. Whilst research has historically focused on the role of the amyloid precursor protein (APP) in the pathogenesis of Alzheimer’s disease, recent advances in trauma research have demonstrated that APP offers considerable neuroprotective properties following TBI, suggesting that APP is an ideal therapeutic candidate. Its acute upregulation following TBI has been shown to serve a beneficial role following trauma and has lead to significant advances in understanding the neuroprotective and neurotrophic functions of APP and its metabolites. Research has focused predominantly on the APP derivative sAPPα, which has consistently demonstrated neuroprotective and neurotrophic functions both in vitro and in vivo following various traumatic insults. Its neuroprotective activity has been narrowed down to a 15 amino acid sequence, and this region is linked to both heparan binding and growth-factor-like properties. It has been proposed that APP binds to heparan sulfate proteoglycans to exert its neuroprotective action. APP presents us with a novel therapeutic compound that could overcome many of the challenges that have stalled development of efficacious TBI treatments previously.

Keywords Amyloid precursor protein      traumatic brain injury      diffuse axonal injury      neuroprotection      heparan sulphate proteoglycans     
Corresponding Authors: Cappai Roberto   
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These authors equally contribute this work

Issue Date: 01 April 2016
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Plummer Stephanie
Van den Heuvel Corinna
Thornton Emma
Corrigan Frances
Cappai Roberto
Cite this article:   
Plummer Stephanie,Van den Heuvel Corinna,Thornton Emma, et al. The Neuroprotective Properties of the Amyloid Precursor Protein Following Traumatic Brain Injury[J]. Aging and disease, 2016, 7(2): 163-179.
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http://www.aginganddisease.org/EN/10.14336/AD.2015.0907     OR     http://www.aginganddisease.org/EN/Y2016/V7/I2/163
Figure 1.  Representation of the structure of APP, highlighting its extracellular, transmembrane and intracellular domains.
Figure 2.  Representation summarising the major pathways of APP proteolytic processing via the α-, β- and γ-secretase enzymes.
Model/MethodIn vitro Neuroprotective & Neurotrophic Functions of sAPPReferences
Cultured rat cortical neuronsEnhances long-term neuronal survival and neuronal extension[84]

Cultured rat hippocampal and septal neurons & human cortical neurons

Protects against hypoglycaemic damage

[67]
Reduces calcium ions; prevents calcium-mediated hypoglycaemia
Protects against glutamate excitotoxicity
Application of Aβ to cultured rat hippocampal neuronsReduces Aβ-induced injury[149]
Attenuates induction of reactive oxygen species
Attenuates elevated intracellular calcium levels
Protects against iron-induced oxidative injury
Cultured embryonic rat hippocampal neuronsSuppresses NMDA-induced currents[99]

Cultured mouse epidermal growth factor responsive neurospheres

Regulates progenitor proliferation in the subventricular zone of lateral ventricle

[102]

Cultured mouse and rat hippocampal neurons

Regulates function of full-length APP in neurite outgrowth

[141]
Table 1  The neuroprotective and neurotrophic functions of sAPP in vitro
Model/MethodIn vivo Neuroprotective & Neurotrophic Functions of sAPPαReferences
TBI models
Impact-acceleration model of diffuse TBI in ratsImproves motor outcome and attenuates axonal injury and neuronal cell loss[124]
Controlled cortical impact (focal) TBI in mice followed by intracerebroventricular infusionImproves motor and cognitive outcome[152]
Significantly improves cortical and hippocampal injury
Controlled cortical impact (focal) TBI in APP-/- mice followed by intracerebroventricular infusionImproves functional outcome, and reduces cortical and hippocampal cell damage[131]
Rescues deficits in APP-/- mice to be no longer significantly different to APP+/+ mice
Weight-drop mechanical percussion model in miceEtazolate, an α-secretase activator, reduces inflammation and cerebral oedema, improves memory and motor outcome and protects tissue[132]
Other injury models (non-TBI)
Four-vessel occlusion model of transient ischaemia in rat hippocampal neuronsProtects against transient cerebral ischaemic brain injury[68]
Lateral ventricle infusion in ratsIncreases synaptic density and memory retention; promotes synaptogenesis[150]
Intracerebroventricular infusionEnhances short- and long-term memory performance[151]
Blocks learning deficits induced by scopolamine
Lateral ventricle infusion in miceIncreases number of epidermal growth factor responsive progenitors through increasing proliferation[102]
Bilateral intrahippocampal electrode and cannula recordings & intrahippocampal infusionFacilitates a role in LTP induction processes in rat dentate gyrus with effect isolated to sAPPα domain of APP[97]
Inhibition of α-secretase reduces LTP whilst exogenous sAPPα rescues it
Endogenous sAPPα is a key contributor to synaptic plasticity and spatial memory
Transgenic mouse model with bovine ADAM10 over-expressionα-secretase over-expression shows neurotrophic effect of cortical cholinergic, glutamatergic and GABAergic presynaptic bouton populations[101]
Table 2  The neuroprotective and neurotrophic functions of sAPP in vivo
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