The neuroprotective domains of the amyloid precursor protein, in traumatic brain injury, are located in the two growth factor domains (original) (raw)
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Neuroprotective effects of sAPPα administration following diffuse traumatic brain injury
2004
Soluble amyloid precursor protein α (sAPPα) is a product of the nonamyloidogenic cleavage pathway of APP that has previously been shown to have many neuroprotective functions in vitro. No study, however, has addressed whether sAPPα may also be neuroprotective in vivo. The present study has therefore examined the in vivo effects of sAPPα administration on axonal injury and neurological outcome following 2-metre impact/ acceleration traumatic brain injury in rats. Treatment with sAPPα at 30 min after injury (icv) significantly reduced axonal injury (AI) within the corpus callosum at 1, 3 and 7 days post-injury and significantly improved motor outcome (rotarod) compared to vehicle treated controls. Our results demonstrate the in vivo neuroprotective properties of post-traumatic administration of sAPPα following traumatic brain injury.
Neuroscience Letters, 2012
Treatment with sAPP␣, the product of non-amyloidogenic processing of the amyloid precursor protein (APP) has been shown to be protective following diffuse traumatic brain injury (TBI), by improving motor outcome and reducing axonal injury. However the effects of treatment with sAPP␣ following a focal TBI have yet to be determined. To investigate this, mice were subjected to a controlled cortical impact injury and treated with either sAPP␣ or its vehicle at 30 min post-injury. Following treatment with sAPP␣ the mice showed a significant improvement in motor and cognitive function early following injury, as determined on the ledged beam and Barnes Maze, respectively, relating to a more rapid rate of recovery. However the effect of treatment with sAPP␣ was not as dramatic as that seen previously following a diffuse injury. Nonetheless, these improvements in functional outcome were acompanied by a small but significant improvement in the amount of cortical and hippocampal at 7 days post-injury, and provide further support for the efficacy of sAPP␣ as a potential neuroprotective agent following TBI.
We have previously shown that following traumatic brain injury (TBI) the presence of the amyloid precursor protein (APP) may be neuroprotective. APP knockout mice have increased neuronal death and worse cognitive and motor outcomes following TBI, which is rescued by treatment with exogenous sAPPa (the secreted ectodomain of APP generated by a-secretase cleavage). Two neuroprotective regions were identified in sAPPa, the N and C-terminal domains D1 and D6a/E2 respectively. As both D1 and D6a/E2 contain heparin binding activity it was hypothesized that this is responsible for the neuroprotective activity. In this study, we focused on the heparin binding site, encompassed by residues 96-110 in D1, which has previously been shown to have neurotrophic properties. We found that treatment
Cellular and Molecular Life Sciences, 2020
Amyloid precursor protein (APP) is a transmembrane protein expressed largely within the central nervous system. Upon cleavage, it does not produce the toxic amyloid peptide (Aβ) only, which is involved in neurodegenerative progressions but via a non-amyloidogenic pathway it is metabolized to produce a soluble fragment (sAPPα) through α-secretase. While a lot of studies are focusing on the role played by APP in the pathogenesis of Alzheimer's disease, sAPPα is reported to have numerous neuroprotective effects and it is being suggested as a candidate with possible therapeutic potential against Alzheimer's disease. However, the mechanisms through which sAPPα precisely works remain elusive. We have presented a comprehensive review of how sAPPα is regulating the neuroprotective effects in different biological models. Moreover, we have focused on the role of sAPPα during different developmental stages of the brain, neurogenic microenvironment in the brain and how this metabolite of APP is regulating the neurogenesis which is regarded as a compelling approach to ameliorate the impaired learning and memory deficits in dementia and diseases like Alzheimer's disease. sAPPα exerts beneficial physiological, biochemical and behavioral effects mitigating the detrimental effects of neurotoxic compounds. It has shown to increase the proliferation rate of numerous cell types and promised the synaptogenesis, neurite outgrowth, cell survival and cell adhesion. Taken together, we believe that further studies are warranted to investigate the exact mechanism of action so that sAPPα could be developed as a novel therapeutic target against neuronal deficits.
Brain Research, 2006
Amyloid precursor protein (APP) has previously been shown to increase following traumatic brain injury (TBI). Whereas a number of investigators assume that increased APP may lead to the production of neurotoxic Aβ and be deleterious to outcome, the soluble α form of APP (sAPPα) is a product of the non-amyloidogenic cleavage of amyloid precursor protein that has previously been shown in vitro to have many neuroprotective and neurotrophic functions. However, no study to date has addressed whether sAPPα may be neuroprotective in vivo. The present study examined the effects of in vivo, posttraumatic sAPPα administration on functional motor outcome, cellular apoptosis, and axonal injury following severe impact-acceleration TBI in rats. Intracerebroventricular administration of sAPPα at 30 min posttrauma significantly improved motor outcome compared to vehicletreated controls as assessed using the rotarod task. Immunohistochemical analysis using antibodies directed toward caspase-3 showed that posttraumatic treatment with sAPPα significantly reduced the number of apoptotic neuronal perikarya within the hippocampal CA3 region and within the cortex 3 days after injury compared to vehicle-treated animals.
A Novel Treatment Approach in Alzheimer’s Disease: sAPPα
Academia Letters, 2021
Alzheimer's disease (AD) is the most common cause of age-related dementia and the number of patients with AD is increasing worldwide. The amyloid cascade hypothesis(ACH) provides a fundamental perspective for the pathogenesis of AD. It is also strongly criticized due to the failure of the clinical trials that experimented with anti-amyloid drugs. Dar et al. brilliantly pointed out that sAPPα could be developed as a novel therapeutic agent in treatment of AD(1). In the ACH model amyloid precursor protein(APP) is cleaved either by β-secretase followed by γ-secretase(amyloidogenic pathway) or α-secretase followed by γ-secretase(nonamyloidogenic pathway). It is the amyloidogenic pathway that ACH mostly focuses on as many studies showed the neurotoxic effects of β-amyloid. However, there is growing evidence showing non-amyloidogenic pathway products have essential roles in several significant physiological processes including neurite growth, learning and memory, neural progenitor cell proliferation, and neural survival(2,3,4,5). Studies by Small et al. and Allinqu ant et al. demonstrate that sAPPα promotes neurite outgrowth(6,7). sAPPα also plays a role in synaptogenesis(8). Zheng et al. showed that APP KO mice display neurological deficits that can be explained by effects on synaptogenesis(9). Zou et al. found that sAPPα is important in maintaining constitutive and adaptive plasticity of dendritic spines in the adult brain(10). sAPPα also demonstrates neuroprotective properties(11). Obregon et al. demonstrated that sAPPα decreases βamyloid by modulating APP processing via BACE1(12). The study showed that while blocking sAPPα increases Aβ production, overexpression of sAPPα decreases amyloid plaques and soluble Aβ. sAPPα also stimulates the proliferation of embryonic neural stem cells(NSCs)(13,14). Studies by Caillé et al. showed that infusion of APP antisense oligonucleotides reduces prolif
Neurobiology of Aging, 2017
Amyloid Precursor Protein (APP), key molecule of Alzheimer disease is metabolized in two antagonist pathways generating the sAPPα having neuroprotective properties and the amyloid peptide (Aß) at the origin of neurotoxic oligomers, particularly Aß1-42. Whether extracellular Aß1-42 oligomers modulate the formation and secretion of sAPPα is not known. We report here that the addition of Aß1-42 oligomers to primary cortical neurons induced a transient increase in alpha secretase activity and secreted sAPPα 6-9 h later. Preventing the generation of sAPPα by using siRNAs for the alpha secretases ADAM10 and ADAM17, or for APP led to increased Aß1-42 oligomer-induced cell death after 24 h. Neuronal injuries due to oxidative stress or growth factor deprivation also generated sAPPα 7h later. Finally, acute injection of Aß1-42 oligomers into wild type mouse hippocampi induced transient secretion of sAPPα 48-72 h later. Altogether, these data suggest that neurons respond to stress by generating sAPPα for their survival. These data must be taken into account when interpreting sAPPα levels as a biomarker in neurological disorders.
Experimental neurology, 2018
One major pathophysiological hallmark of Alzheimer's disease (AD) is senile plaques composed of amyloid β (Aβ). In the amyloidogenic pathway, cleavage of the amyloid precursor protein (APP) is shifted towards Aβ production and soluble APPβ (sAPPβ) levels. Aβ is known to impair synaptic function; however, much less is known about the physiological functions of sAPPβ. The neurotrophic properties of sAPPα, derived from the non-amyloidogenic pathway of APP cleavage, are well-established, whereas only a few, conflicting studies on sAPPβ exist. The intracellular pathways of sAPPβ are largely unknown. Since sAPPβ is generated alongside Aβ by β-secretase (BACE1) cleavage, we tested the hypothesis that sAPPβ effects differ from sAPPα effects as a neurotrophic factor. We therefore performed a head-to-head comparison of both mammalian recombinant peptides in developing primary hippocampal neurons (PHN). We found that sAPPα significantly increases axon length (p = 0.0002) and that both sAPP...