Deciphering the neuroprotective and neurogenic potential of soluble amyloid precursor protein alpha (sAPPα) (original) (raw)
Related papers
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
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 sAPPα and sAPPβ increase neurite number (p < 0.0001) of PHN at 7 days in culture (DIV7) but not at DIV4. Moreover, both sAPPα-and sAPPβ-treated neurons showed a higher neuritic complexity in Sholl analysis. The number of glutamatergic synapses (p < 0.0001), as well as layer thickness of postsynaptic densities (PSDs), were significantly increased, and GABAergic synapses decreased upon sAPP overexpression in PHN. Furthermore, we showed that sAPPα enhances ERK and CREB1 phosphorylation upon glutamate stimulation at DIV7, but not DIV4 or DIV14. These neurotrophic effects are further associated with increased glutamate sensitivity and CREB1-signaling. Finally, we found that sAPPα levels are significantly reduced in brain homogenates of AD patients compared to control subjects. Taken together, our data indicate critical stage-dependent roles of sAPPs in the developing glutamatergic system in vitro, which might help to understand deleterious consequences of altered APP shedding in AD patients, beyond Aβ pathophysiology.
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...
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.
Journal of neuroscience research, 2016
Soluble amyloid precursor protein α (sAPPα), a secreted proteolytic fragment of nonamyloidogenic amyloid precursor protein (APP) processing, is known for numerous neuroprotective functions. These functions include but are not limited to proliferation, neuroprotection, synaptic plasticity, memory formation, neurogenesis, and neuritogenesis in cell culture and animal models. In addition, sAPPα influences amyloid-β (Aβ) production by direct modulation of APP β-secretase proteolysis as well as Aβ-related or unrelated tau pathology, hallmark pathologies of Alzheimer's disease (AD). Thus, the restoration of sAPPα levels and functions in the brain by increasing nonamyloidogenic APP processing and/or manipulation of its signaling could reduce AD pathology and cognitive impairment. It is likely that identification and characterization of sAPPα receptors in the brain, downstream effectors, and signaling pathways will pave the way for an attractive therapeutic target for AD prevention or i...
sAPPα antagonizes dendritic degeneration and neuron death triggered by proteasomal stress
Molecular and Cellular Neuroscience, 2010
Impaired proteasomal function is a major hallmark in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD). Here we investigated the biological properties of the secreted cleavage product of APP (sAPPα) in antagonizing stress signalling, dendritic degeneration and neuronal cell death induced by the proteasome inhibitor epoxomicin. Analysis of executioner caspase activation demonstrated that sAPPα was able to protect PC12 cells from apoptosis triggered by epoxomicin, as well as by genotoxic stress (UV irradiation). This anti-apoptotic effect of sAPPα was associated with inhibition of the stresstriggered c-Jun N-terminal kinase (JNK)-signalling pathway. The anti-apoptotic effect of sAPPα could also be confirmed in organotypic slice cultures of Thy1-GFP mouse hippocampi. Confocal time-lapse imaging of CA1 pyramidal neurons revealed that preincubation with sAPPα preserves the structural integrity of neurons after epoxomicin treatment. Taken together, our data demonstrate that sAPPα is neuroprotective under conditions of proteasomal stress.
sAPP Enhances the Transdifferentiation of Adult Bone Marrow Progenitor Cells to Neuronal Phenotypes
Current Alzheimer Research, 2006
The remediation of neurodegeneration and cognitive decline in Alzheimer's Disease (AD) remains a challenge to basic scientists and clinicians. It has been suggested that adult bone marrow stem cells can transdifferentiate into different neuronal phenotypes. Here we demonstrate that the α-secretase-cleaved fragment of the amyloid precursor protein (sAPPα), a potent neurotrophic factor, potentiates the nerve growth factor (NGF)/retinoic acid (RA) induced transdifferentiation of bone marrow-derived adult progenitor cells (MAPCs) into neural progenitor cells and, more specifically, enhances their terminal differentiation into a cholinergic-like neuronal phenotype. The addition of sAPPα to NGF/RAstimulated MAPCs resulted in their conversion to neuronal-like cells as evidenced by the extension of neurites and the appearance of immature synaptic complexes. MAPCs differentiated in the presence of sAPPα and NGF/RA exhibited a 40% to as much as 75% increase in neuronal proteins including NeuN, β-tubulin III, NFM, and synaptophysin, compared to MAPCs differentiated by NGF/RA alone. This process was accompanied by an increase in the levels of choline acetyltransferase, a marker of cholinergic neurons, compared to those of GABAergic and dopaminergic neuronal subtypes. MAPCs immunpositive for sAPPα were identified within the septohippocampal system of transgenic PS/APP mice injected intravenously with sAPPα-transfected MAPCs and found in close proximity to the cerebral vasculature. Given that in AD cholinergic neurons are severely vulnerable to neurodegeneration and that the levels of sAPPα are significantly reduced, these findings suggest the combined use of sAPPα and MAPCs offers a new and potentially powerful therapeutic strategy for AD treatment.
BMC Genomics, 2013
Background: Differential processing of the amyloid precursor protein liberates either amyloid-ß, a causative agent of Alzheimer's disease, or secreted amyloid precursor protein-alpha (sAPPα), which promotes neuroprotection, neurotrophism, neurogenesis and synaptic plasticity. The underlying molecular mechanisms recruited by sAPPα that underpin these considerable cellular effects are not well elucidated. As these effects are enduring, we hypothesised that regulation of gene expression may be of importance and examined temporally specific gene networks and pathways induced by sAPPα in rat hippocampal organotypic slice cultures. Slices were exposed to 1 nM sAPPα or phosphate buffered saline for 15 min, 2 h or 24 h and sAPPα-associated gene expression profiles were produced for each time-point using Affymetrix Rat Gene 1.0 ST arrays (moderated t-test using Limma: p < 0.05, and fold change ± 1.15). Results: Treatment of organotypic hippocampal slice cultures with 1 nM sAPPα induced temporally distinct gene expression profiles, including mRNA and microRNA associated with Alzheimer's disease. Having demonstrated that treatment with human recombinant sAPPα was protective against N-methyl D-aspartate-induced toxicity, we next explored the sAPPα-induced gene expression profiles. Ingenuity Pathway Analysis predicted that short-term exposure to sAPPα elicited a multi-level transcriptional response, including upregulation of immediate early gene transcription factors (AP-1, Egr1), modulation of the chromatin environment, and apparent activation of the constitutive transcription factors CREB and NF-κB. Importantly, dynamic regulation of NF-κB appears to be integral to the transcriptional response across all time-points. In contrast, medium and long exposure to sAPPα resulted in an overall downregulation of gene expression. While these results suggest commonality between sAPPα and our previously reported analysis of plasticity-related gene expression, we found little crossover between these datasets. The gene networks formed following medium and long exposure to sAPPα were associated with inflammatory response, apoptosis, neurogenesis and cell survival; functions likely to be the basis of the neuroprotective effects of sAPPα.