ArticleThe Journal of biological chemistry2013
Interplay between α-, β-, and γ-secretases determines biphasic amyloid-β protein level in the presence of a γ-secretase inhibitor.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
- Has inhibition of Aβ production adequately been tested as therapeutic approach in mild AD? A model-based meta-analysis of γ-secretase inhibitor data.European journal of clinical pharmacology · 2013Pooled it
- LRRK2 deficiency mitigates amyloid β deposition-mediated pathology in a murine Alzheimer's disease model by reprogramming microglia.Translational psychiatry · 2025Article
- Unraveling Molecular Targets for Neurodegenerative Diseases ThroughInternational journal of molecular sciences · 2025Review
- Altered synaptic plasticity at hippocampal CA1-CA3 synapses in Alzheimer's disease: integration of amyloid precursor protein intracellular domain and amyloid beta effects into computational models.Frontiers in computational neuroscience · 2023Article
- Importance of CSF-based Aβ clearance with age in humans increases with declining efficacy of blood-brain barrier/proteolytic pathways.Communications biology · 2022Article
- Modeling Neurotransmission: Computational Tools to Investigate Neurological Disorders.International journal of molecular sciences · 2021Review
- Bridging Scales in Alzheimer's Disease: Biological Framework for Brain Simulation With The Virtual Brain.Frontiers in neuroinformatics · 2021Review
- P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases.International journal of molecular sciences · 2020Review
- Best Practices to Maximize the Use and Reuse of Quantitative and Systems Pharmacology Models: Recommendations From the United Kingdom Quantitative and Systems Pharmacology Network.CPT: pharmacometrics & systems pharmacology · 2019Article
- Emerging Signal Regulating Potential of Genistein Against Alzheimer's Disease: A Promising Molecule of Interest.Frontiers in cell and developmental biology · 2019Review
- Quantitative Systems Pharmacology Model for Alzheimer Disease Indicates Targeting Sphingolipid Dysregulation as Potential Treatment Option.CPT: pharmacometrics & systems pharmacology · 2018Article
- Computational modeling and biomarker studies of pharmacological treatment of Alzheimer's disease (Review).Molecular medicine reports · 2018Review
- Exosomes: a novel therapeutic target for Alzheimer's disease?Neural regeneration research · 2018Article
- A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human.CPT: pharmacometrics & systems pharmacology · 2017Article
- The Impact of Mathematical Modeling in Understanding the Mechanisms Underlying Neurodegeneration: Evolving Dimensions and Future Directions.CPT: pharmacometrics & systems pharmacology · 2017Review
- Kinase Inhibition Leads to Hormesis in a Dual Phosphorylation-Dephosphorylation Cycle.PLoS computational biology · 2016Article
- Abeta, oxidative stress in Alzheimer disease: evidence based on proteomics studies.Biochimica et biophysica acta · 2014Review
- CNS amyloid-β, soluble APP-α and -β kinetics during BACE inhibition.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2014Article
- Plasma amyloid beta measurements - a desired but elusive Alzheimer's disease biomarker.Alzheimer's research & therapy · 2013Review
- Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Amyloid-β (Aβ) is produced by the consecutive cleavage of amyloid precursor protein (APP) first by β-secretase, generating C99, and then by γ-secretase. APP is also cleaved by α-secretase. It is hypothesized that reducing the production of Aβ in the brain may slow the progression of Alzheimer disease. Therefore, different γ-secretase inhibitors have been developed to reduce Aβ production. Paradoxically, it has been shown that low to moderate inhibitor concentrations cause a rise in Aβ production in different cell lines, in different animal models, and also in humans. A mechanistic understanding of the Aβ rise remains elusive. Here, a minimal mathematical model has been developed that quantitatively describes the Aβ dynamics in cell lines that exhibit the rise as well as in cell lines that do not. The model includes steps of APP processing through both the so-called amyloidogenic pathway and the so-called non-amyloidogenic pathway. It is shown that the cross-talk between these two pathways accounts for the increase in Aβ production in response to inhibitor, i.e. an increase in C99 will inhibit the non-amyloidogenic pathway, redirecting APP to be cleaved by β-secretase, leading to an additional increase in C99 that overcomes the loss in γ-secretase activity. With a minor extension, the model also describes plasma Aβ profiles observed in humans upon dosing with a γ-secretase inhibitor. In conclusion, this mechanistic model rationalizes a series of experimental results that spans from in vitro to in vivo and to humans. This has important implications for the development of drugs targeting Aβ production in Alzheimer disease.
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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.