Amyloid Precursor Protein Modulates Beta-Catenin Degradation
Amyloid Precursor Protein Modulates Beta-Catenin Degradation
Background: The amyloid precursor protein (APP) is genetically associated with Alzheimer's disease (AD). Elucidating the function of APP should help understand AD pathogenesis and provide insights into therapeutic designs against this devastating neurodegenerative disease.
Results: We demonstrate that APP expression in primary neurons induces β-catenin phosphorylation at Ser33, Ser37, and Thr41 (S33/37/T41) residues, which is a prerequisite for β-catenin ubiquitinylation and proteasomal degradation. APP-induced phosphorylation of β-catenin resulted in the reduction of total β-catenin levels, suggesting that APP expression promotes β-catenin degradation. In contrast, treatment of neurons with APP siRNAs increased total β-catenin levels and decreased β-catenin phosphorylation at residues S33/37/T41. Further, β-catenin was dramatically increased in hippocampal CA1 pyramidal cells from APP knockout animals. Acute expression of wild type APP or of familial AD APP mutants in primary neurons downregulated β-catenin in membrane and cytosolic fractions, and did not appear to affect nuclear β-catenin or β-catenin-dependent transcription. Conversely, in APP knockout CA1 pyramidal cells, accumulation of β-catenin was associated with the upregulation of cyclin D1, a downstream target of β-catenin signaling. Together, these data establish that APP downregulates β-catenin and suggest a role for APP in sustaining neuronal function by preventing cell cycle reactivation and maintaining synaptic integrity.
Conclusion: We have provided strong evidence that APP modulates β-catenin degradation in vitro and in vivo. Future studies may investigate whether APP processing is necessary for β-catenin downregulation, and determine if excessive APP expression contributes to AD pathogenesis through abnormal β-catenin downregulation.
β-Catenin plays a central role in Wnt signalling in the canonical pathway. In the absence of Wnt signalling, cytoplasmic β-catenin exists in a complex together with axin, adenomatous polyposis coli (APC), and glycogen synthase kinase (GSK)-3β. GSK-3β constitutively phosphorylates β-catenin at Ser33, Ser37, and Thr41 (S33/37/T41) residues, triggering ubiquitinylation by a Cullin-1-containing E3 ligase (also known as the SCF complex) before proteasomal degradation. Signalling by Wnt through Frizzled and LRP cell surface receptors inhibits GSK-3β and stabilizes β-catenin. When stabilized, β-catenin translocates to the nucleus and functions as a transcription cofactor of the T cell factor (TCF), activating responsive genes such as cyclin D1 and c-myc.
Several lines of evidence suggest that APP influences β-catenin regulation. APP binds to APP-BP1 which activates the small ubiquitin-like protein Nedd8. Activated Nedd8 modifies Cullins which then becomes more stable. When Cullin-1 in SCF is transiently stabilized, it increases β-catenin ubiquitinylation and degradation. In addition, APP plays an important role in cell-cell adhesion, a function that may involve β-catenin. Membrane-associated β-catenin anchors cadherins to the actin cytoskeleton. Interactions with cadherins may underlie an important role for β-catenin in synaptic integrity of neurons. Synaptic dysfunction is one of the earliest events in AD pathogenesis, and APP appears to contribute to synapse formation or stabilization.
Both APP and Presenilins are genetically associated with AD. In addition to its role in APP processing, Presenilin-1 (PS1) also interacts with the cadherin/catenin adhesion complex and affects β-catenin delivery to the membrane adhesion complex. There is some controversy surrounding the influence of PS1 and its FAD mutants on β-catenin. Similarly, different levels of β-catenin have been reported in AD. This is likely attributable to the complexity of these systems made possible by multimodal interactions between APP, PS1, β-catenin, and E-cadherin; a complexity that justifies more detailed analyses of these systems. The purpose of this report is to determine whether APP mediates β-catenin degradation in vitro and in vivo. We provide critical evidence that APP downregulates β-catenin in neurons.
Background: The amyloid precursor protein (APP) is genetically associated with Alzheimer's disease (AD). Elucidating the function of APP should help understand AD pathogenesis and provide insights into therapeutic designs against this devastating neurodegenerative disease.
Results: We demonstrate that APP expression in primary neurons induces β-catenin phosphorylation at Ser33, Ser37, and Thr41 (S33/37/T41) residues, which is a prerequisite for β-catenin ubiquitinylation and proteasomal degradation. APP-induced phosphorylation of β-catenin resulted in the reduction of total β-catenin levels, suggesting that APP expression promotes β-catenin degradation. In contrast, treatment of neurons with APP siRNAs increased total β-catenin levels and decreased β-catenin phosphorylation at residues S33/37/T41. Further, β-catenin was dramatically increased in hippocampal CA1 pyramidal cells from APP knockout animals. Acute expression of wild type APP or of familial AD APP mutants in primary neurons downregulated β-catenin in membrane and cytosolic fractions, and did not appear to affect nuclear β-catenin or β-catenin-dependent transcription. Conversely, in APP knockout CA1 pyramidal cells, accumulation of β-catenin was associated with the upregulation of cyclin D1, a downstream target of β-catenin signaling. Together, these data establish that APP downregulates β-catenin and suggest a role for APP in sustaining neuronal function by preventing cell cycle reactivation and maintaining synaptic integrity.
Conclusion: We have provided strong evidence that APP modulates β-catenin degradation in vitro and in vivo. Future studies may investigate whether APP processing is necessary for β-catenin downregulation, and determine if excessive APP expression contributes to AD pathogenesis through abnormal β-catenin downregulation.
β-Catenin plays a central role in Wnt signalling in the canonical pathway. In the absence of Wnt signalling, cytoplasmic β-catenin exists in a complex together with axin, adenomatous polyposis coli (APC), and glycogen synthase kinase (GSK)-3β. GSK-3β constitutively phosphorylates β-catenin at Ser33, Ser37, and Thr41 (S33/37/T41) residues, triggering ubiquitinylation by a Cullin-1-containing E3 ligase (also known as the SCF complex) before proteasomal degradation. Signalling by Wnt through Frizzled and LRP cell surface receptors inhibits GSK-3β and stabilizes β-catenin. When stabilized, β-catenin translocates to the nucleus and functions as a transcription cofactor of the T cell factor (TCF), activating responsive genes such as cyclin D1 and c-myc.
Several lines of evidence suggest that APP influences β-catenin regulation. APP binds to APP-BP1 which activates the small ubiquitin-like protein Nedd8. Activated Nedd8 modifies Cullins which then becomes more stable. When Cullin-1 in SCF is transiently stabilized, it increases β-catenin ubiquitinylation and degradation. In addition, APP plays an important role in cell-cell adhesion, a function that may involve β-catenin. Membrane-associated β-catenin anchors cadherins to the actin cytoskeleton. Interactions with cadherins may underlie an important role for β-catenin in synaptic integrity of neurons. Synaptic dysfunction is one of the earliest events in AD pathogenesis, and APP appears to contribute to synapse formation or stabilization.
Both APP and Presenilins are genetically associated with AD. In addition to its role in APP processing, Presenilin-1 (PS1) also interacts with the cadherin/catenin adhesion complex and affects β-catenin delivery to the membrane adhesion complex. There is some controversy surrounding the influence of PS1 and its FAD mutants on β-catenin. Similarly, different levels of β-catenin have been reported in AD. This is likely attributable to the complexity of these systems made possible by multimodal interactions between APP, PS1, β-catenin, and E-cadherin; a complexity that justifies more detailed analyses of these systems. The purpose of this report is to determine whether APP mediates β-catenin degradation in vitro and in vivo. We provide critical evidence that APP downregulates β-catenin in neurons.
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