ArticleThe Journal of biological chemistry2014
Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in SH-SY5Y neuroblastoma cells.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 49 citations in OpenAlex.
- Aβ Modulates Extracellular Vesicles Proteomic Profile Impacting Phosphorylation Mediators.Molecular neurobiology · 2025Article
- Elevated BACE1 mRNA Level is Associated with Lower miR-15a-5p and miR-19b-3p Expressions in Peripheral Blood Mononuclear Cells of Patients with Late-Onset Alzheimer's Disease: Wet Lab Results and Bioinformatics Analysis.Molecular neurobiology · 2025Article
- Cell-specific copper dyshomeostasis mechanism in Alzheimer's disease.Translational neurodegeneration · 2025Review
- Review
- Protein modification in neurodegenerative diseases.MedComm · 2024Review
- Potential Implications of miRNAs in the Pathogenesis, Diagnosis, and Therapeutics of Alzheimer's Disease.International journal of molecular sciences · 2023Review
- The Multifaceted Role of WNT Signaling in Alzheimer's Disease Onset and Age-Related Progression.Cells · 2023Review
- Exposure of metal toxicity in Alzheimer's disease: An extensive review.Frontiers in pharmacology · 2022Review
- Role of neurotoxicants in the pathogenesis of Alzheimer's disease: a mechanistic insight.Annals of medicine · 2021Review
- Article
- Phosphorylation Signaling in APP Processing in Alzheimer's Disease.International journal of molecular sciences · 2019Review
- Multi-Loop Model of Alzheimer Disease: An Integrated Perspective on the Wnt/GSK3β, α-Synuclein, and Type 3 Diabetes Hypotheses.Frontiers in aging neuroscience · 2019Article
- Inhibition of SIRT2 by Targeting GSK3β-Mediated Phosphorylation Alleviates SIRT2 Toxicity in SH-SY5Y Cells.Frontiers in cellular neuroscience · 2019Article
- Copper signaling in the brain and beyond.The Journal of biological chemistry · 2018Review
- Advances in Multi-Functional Ligands and the Need for Metal-Related Pharmacology for the Management of Alzheimer Disease.Frontiers in pharmacology · 2018Review
- Structure and Synaptic Function of Metal Binding to the Amyloid Precursor Protein and its Proteolytic Fragments.Frontiers in molecular neuroscience · 2017Review
- Gene expression patterns in the progression of canine copper-associated chronic hepatitis.PloS one · 2017Article
- Biometal Dyshomeostasis and Toxic Metal Accumulations in the Development of Alzheimer's Disease.Frontiers in molecular neuroscience · 2017Review
- Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance.Acta pharmacologica Sinica · 2016Article
- Tau pathology-mediated presynaptic dysfunction.Neuroscience · 2016Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Amyloid precursor protein (APP) undergoes post-translational modification, including O- and N-glycosylation, ubiquitination, and phosphorylation as it traffics through the secretory pathway. We have previously reported that copper promotes a change in the cellular localization of APP. We now report that copper increases the phosphorylation of endogenous APP at threonine 668 (Thr-668) in SH-SY5Y neuronal cells. The level of APPT668-p (detected using a phospho-site-specific antibody) exhibited a copper-dependent increase. Using confocal microscopy imaging we demonstrate that the phospho-deficient mutant, Thr-668 to alanine (T668A), does not exhibit detectable copper-responsive APP trafficking. In contrast, mutating a serine to an alanine at residue 655 does not affect copper-responsive trafficking. We further investigated the importance of the Thr-668 residue in copper-responsive trafficking by treating SH-SY5Y cells with inhibitors for glycogen synthase kinase 3-β (GSK3β) and cyclin-dependent kinases (Cdk), the main kinases that phosphorylate APP at Thr-668 in neurons. Our results show that the GSK3β kinase inhibitors LiCl, SB 216763, and SB 415286 prevent copper-responsive APP trafficking. In contrast, the Cdk inhibitors Purvalanol A and B had no significant effect on copper-responsive trafficking in SH-SY5Y cells. In cultured primary hippocampal neurons, copper promoted APP re-localization to the axon, and this effect was inhibited by the addition of LiCl, indicating that a lithium-sensitive kinase(s) is involved in copper-responsive trafficking in hippocampal neurons. This is consistent with APP axonal transport to the synapse, where APP is involved in a number of functions. We conclude that copper promotes APP trafficking by promoting a GSK3β-dependent phosphorylation in SH-SY5Y cells.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.