ArticlePloS one2014
Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
16 citing papers in PubMed, 33 citations in OpenAlex.
- Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol.Cell & bioscience · 2023Review
- APP family member dimeric complexes are formed predominantly in synaptic compartments.Cell & bioscience · 2023Article
- An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations.Biophysical journal · 2022Article
- Aß40 displays amyloidogenic properties in the non-transgenic mouse brain but does not exacerbate Aß42 toxicity in Drosophila.Alzheimer's research & therapy · 2020Article
- Bicelles Rich in both Sphingolipids and Cholesterol and Their Use in Studies of Membrane Proteins.Journal of the American Chemical Society · 2020Article
- γ-Secretase modulators exhibit selectivity for modulation of APP cleavage but inverse γ-secretase modulators do not.Alzheimer's research & therapy · 2020Article
- Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA.Cellular and molecular life sciences : CMLS · 2018Article
- Backbone Hydrogen Bond Strengths Can Vary Widely in Transmembrane Helices.Journal of the American Chemical Society · 2017Article
- γ-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct.EMBO molecular medicine · 2017Article
- LRP1 Modulates APP Intraneuronal Transport and Processing in Its Monomeric and Dimeric State.Frontiers in molecular neuroscience · 2017Article
- Transmembrane Substrate Determinants for γ-Secretase Processing of APP CTFβ.Biochemistry · 2016Article
- Transthyretin Suppresses Amyloid-β Secretion by Interfering with Processing of the Amyloid-β Protein Precursor.Journal of Alzheimer's disease : JAD · 2016Article
- Phosphatidylethanolamine Metabolism in Health and Disease.International review of cell and molecular biology · 2016Review
- Effects and possible mechanisms of action of acacetin on the behavior and eye morphology of Drosophila models of Alzheimer's disease.Scientific reports · 2015Article
- Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator.Molecular neurodegeneration · 2015Article
- Analysis by a highly sensitive split luciferase assay of the regions involved in APP dimerization and its impact on processing.FEBS open bio · 2015Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Altered production of β-amyloid (Aβ) from the amyloid precursor protein (APP) is closely associated with Alzheimer's disease (AD). APP has a number of homo- and hetero-dimerizing domains, and studies have suggested that dimerization of β-secretase derived APP carboxyl terminal fragment (CTFβ, C99) impairs processive cleavage by γ-secretase increasing production of long Aβs (e.g., Aβ1-42, 43). Other studies report that APP CTFβ dimers are not γ-secretase substrates. We revisited this issue due to observations made with an artificial APP mutant referred to as 3xK-APP, which contains three lysine residues at the border of the APP ectodomain and transmembrane domain (TMD). This mutant, which dramatically increases production of long Aβ, was found to form SDS-stable APP dimers, once again suggesting a mechanistic link between dimerization and increased production of long Aβ. To further evaluate how multimerization of substrate affects both initial γ-secretase cleavage and subsequent processivity, we generated recombinant wild type- (WT) and 3xK-C100 substrates, isolated monomeric, dimeric and trimeric forms of these proteins, and evaluated both ε-cleavage site utilization and Aβ production. These show that multimerization significantly impedes γ-secretase cleavage, irrespective of substrate sequence. Further, the monomeric form of the 3xK-C100 mutant increased long Aβ production without altering the initial ε-cleavage utilization. These data confirm and extend previous studies showing that dimeric substrates are not efficient γ-secretase substrates, and demonstrate that primary sequence determinants within APP substrate alter γ-secretase processivity.
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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.