ArticleThe Journal of biological chemistry2010
Dual role of alpha-secretase cleavage in the regulation of gamma-secretase activity for amyloid production.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 42 citations in OpenAlex.
- Trial
- APP-BACE1 Interaction and Intracellular Localization Regulate Aβ Production in iPSC-Derived Cortical Neurons.Cellular and molecular neurobiology · 2023Article
- The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration.International journal of molecular sciences · 2023Article
- The role of Aβ in Alzheimer's Disease as an Evolutionary Outcome of Optimized Innate Immune Defense.The journal of prevention of Alzheimer's disease · 2022Article
- Article
- A Pentacyclic Triterpene fromACS chemical neuroscience · 2020Article
- A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease.Molecular psychiatry · 2020Article
- Emerging Alternative Proteinases in APP Metabolism and Alzheimer's Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP.Frontiers in aging neuroscience · 2019Review
- The role of astrocytes in amyloid production and Alzheimer's disease.Open biology · 2017Review
- A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis.The Journal of biological chemistry · 2016Review
- Imaging and Functional Analysis of γ-Secretase and Substrate in a Proteolipobead System with an Activity-Based Probe.Analytical chemistry · 2016Article
- Dynamic self-guiding analysis of Alzheimer's disease.Oncotarget · 2015Review
- Differential release of β-amyloid from dendrite- versus axon-targeted APP.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2014Article
- Complex regulation of γ-secretase: from obligatory to modulatory subunits.Frontiers in aging neuroscience · 2014Review
- Article
- Neprilysin and Aβ Clearance: Impact of the APP Intracellular Domain in NEP Regulation and Implications in Alzheimer's Disease.Frontiers in aging neuroscience · 2013Review
- Next generation therapeutics for Alzheimer's disease.EMBO molecular medicine · 2013Article
- Development and mechanism of γ-secretase modulators for Alzheimer's disease.Biochemistry · 2013Review
- AβPP-selective BACE inhibitors (ASBI): novel class of therapeutic agents for alzheimer's disease.Journal of Alzheimer's disease : JAD · 2013Article
- Advances in the pathogenesis of Alzheimer's disease: a re-evaluation of amyloid cascade hypothesis.Translational neurodegeneration · 2012Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Processing of the amyloid precursor protein (APP) by β- and γ-secretases generates pathogenic β-amyloid (Aβ) peptides associated with Alzheimer disease (AD), whereas cleavage of APP by α-secretases precludes Aβ formation. Little is known about the role of α-secretase cleavage in γ-secretase regulation. Here, we show that α-secretase-cleaved APP C-terminal product (αCTF) functions as an inhibitor of γ-secretase. We demonstrate that the substrate inhibitory domain (ASID) within αCTF, which is bisected by the α-secretase cleavage site, contributes to this negative regulation because deleting or masking this domain turns αCTF into a better substrate for γ-secretase. Moreover, α-secretase cleavage can potentiate the inhibitory effect of ASID. Inhibition of γ-secretase activity by αCTF is observed in both in vitro and cellular systems. This work reveals an unforeseen role for α-secretase in generating an endogenous γ-secretase inhibitor that down-regulates the production of Aβ. Deregulation of this feedback mechanism may contribute to the pathogenesis of AD.
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Registered trials
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.