ArticleCellular and molecular life sciences : CMLS2012
APP dimer formation is initiated in the endoplasmic reticulum and differs between APP isoforms.
Article in Cellular and molecular life sciences : CMLS, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 41 citations in OpenAlex.
- Molecular Glue Degraders Enhance CAPRIN1-Dependent Lysosomal Degradation of APP and Reduce Amyloid β in Alzheimer's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Intracellular protein GBF1 displays significant associations with amyloid pathology in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Review
- Delineating the Role of GxxxG Motif in Amyloidogenesis: A New Perspective in Targeting Amyloid-Beta Mediated AD Pathogenesis.ACS bio & med chem Au · 2024Review
- Electrical signals in the ER are cell type and stimulus specific with extreme spatial compartmentalization in neurons.Cell reports · 2023Article
- Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders.Pharmacological reviews · 2022Review
- Structural biology of cell surface receptors implicated in Alzheimer's disease.Biophysical reviews · 2022Review
- Secretases Related to Amyloid Precursor Protein Processing.Membranes · 2021Review
- Activity of Selected Group of Monoterpenes in Alzheimer's Disease Symptoms in Experimental Model Studies-A Non-Systematic Review.International journal of molecular sciences · 2021Review
- Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperoneFrontiers in cell and developmental biology · 2021Article
- Receptor-mediated endocytosis 8 (RME-8)/DNAJC13 is a novel positive modulator of autophagy and stabilizes cellular protein homeostasis.Cellular and molecular life sciences : CMLS · 2021Article
- The amyloid precursor protein affects glyceraldehyde 3-phosphate dehydrogenase levels, organelle localisation and thermal stability.Molecular biology reports · 2020Article
- Biochemical Markers in Alzheimer's Disease.International journal of molecular sciences · 2020Review
- Amyloid Precursor Protein Dimerisation Reduces Neurite Outgrowth.Molecular neurobiology · 2019Article
- The product of the γ-secretase processing of ephrinB2 regulates VE-cadherin complexes and angiogenesis.Cellular and molecular life sciences : CMLS · 2018Article
- Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA.Cellular and molecular life sciences : CMLS · 2018Article
- C-terminal fragments of the amyloid precursor protein in cerebrospinal fluid as potential biomarkers for Alzheimer disease.Scientific reports · 2017Article
- Structure and Synaptic Function of Metal Binding to the Amyloid Precursor Protein and its Proteolytic Fragments.Frontiers in molecular neuroscience · 2017Review
- LRP1 Modulates APP Intraneuronal Transport and Processing in Its Monomeric and Dimeric State.Frontiers in molecular neuroscience · 2017Article
- Association of TrkA and APP Is Promoted by NGF and Reduced by Cell Death-Promoting Agents.Frontiers in molecular neuroscience · 2017Article
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Authors and funding
8 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The amyloid precursor protein (APP) is part of a larger gene family, which has been found to form homo- or heterotypic complexes with its homologues, whereby the exact molecular mechanism and origin of dimer formation remains elusive. In order to assess the cellular location of dimerization, we have generated a cell culture model system in CHO-K1 cells, stably expressing human APP, harboring dilysine-based organelle sorting motifs [KKAA-endoplasmic reticulum (ER); KKFF-Golgi], accomplishing retention within early secretory compartments. We show that APP exists as disulfide-bonded dimers upon ER retention after it was isolated from cells, and analyzed by SDS-polyacrylamide gel electrophoresis under non-reducing conditions. In contrast, strong denaturing and reducing conditions, or deletion of the E1 domain, resulted in the disappearance of those dimers. Thus we provide first evidence that a fraction of APP can associate via intermolecular disulfide bonds, likely generated between cysteines located in the extracellular E1 domain. We particularly visualize APP dimerization itself and identified the ER as subcellular compartment of its origin using biochemical or split GFP approaches. Interestingly, we also found that minor amounts of SDS-resistant APP dimers were located to the cell surface, revealing that once generated in the oxidative environment of the ER, dimers remained stably associated during transport. In addition, we show that APP isoforms encompassing the Kunitz-type protease inhibitor (KPI) domain exhibit a strongly reduced ability to form cis-directed dimers in the ER, whereas trans-mediated cell aggregation of Drosophila Schneider S2-cells was isoform independent. Thus, suggesting that steric properties of KPI-APP might be the cause for weaker cis-interaction in the ER, compared to APP695. Finally, we provide evidence that APP/APLP1 heterointeractions are likewise initiated in the ER.
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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.