ArticleThe Journal of biological chemistry2014
γ-Secretase associated with lipid rafts: multiple interactive pathways in the stepwise processing of β-carboxyl-terminal fragment.
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 49 papers.
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Who cites it
49 citing papers in PubMed.
- The γ-secretase complex: from discovery to a therapeutic target.RSC chemical biology · 2026Review
- Divergent Roles of mGlu2 and mGlu3 Receptors in Amyloid-β Production and Cognitive Dysfunctions in Alzheimer's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Reduced serum AHR agonistic activity reflects amyloid dysregulation in AT1 subtypes of Alzheimer's disease.Alzheimer's research & therapy · 2026Article
- The amyloid beta 42/38 ratio as a plasma biomarker of early memory deficits in cognitively unimpaired older adults.Neurobiology of aging · 2024Article
- β-Amyloid species production and tau phosphorylation in iPSC-neurons with reference to neuropathologically characterized matched donor brains.Journal of neuropathology and experimental neurology · 2024Article
- Article
- The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aβ43 and atypical clinical manifestations.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Integrative Single-Plaque Analysis Reveals Signature Aβ and Lipid Profiles in the Alzheimer's Brain.Analytical chemistry · 2024Article
- Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform.Nature communications · 2024Article
- Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.bioRxiv : the preprint server for biology · 2024Article
- APP substrate ectodomain defines amyloid-β peptide length by restraining γ-secretase processivity and facilitating product release.The EMBO journal · 2023Article
- Amyloid fibril proteomics of AD brains reveals modifiers of aggregation and toxicity.Molecular neurodegeneration · 2023Article
- Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol.Cell & bioscience · 2023Review
- Mass Spectrometry Imaging in Alzheimer's Disease.Brain connectivity · 2023Article
- Different transmembrane domains determine the specificity and efficiency of the cleavage activity of the γ-secretase subunit presenilin.The Journal of biological chemistry · 2023Article
- Review
- Gamma-secretase modulators: a promising route for the treatment of Alzheimer's disease.Frontiers in molecular neuroscience · 2023Review
- Amyloid β, Lipid Metabolism, Basal Cholinergic System, and Therapeutics in Alzheimer's Disease.International journal of molecular sciences · 2022Review
- γ-Secretase in Alzheimer's disease.Experimental & molecular medicine · 2022Review
- Heads Up! Interlinked Amyloidogenic and Axonal Transport Pathways in Concussion-Induced Neurodegeneration.Neuroscience insights · 2022Article
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
γ-Secretase generates amyloid β-protein (Aβ), a pathogenic molecule in Alzheimer disease, through the intramembrane cleavage of the β-carboxyl-terminal fragment (βCTF) of β-amyloid precursor protein. We previously showed the framework of the γ-secretase cleavage, i.e. the stepwise successive processing of βCTF at every three (or four) amino acids. However, the membrane integrity of γ-secretase was not taken into consideration because of the use of the 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonic acid-solubilized reconstituted γ-secretase system. Here, we sought to address how the membrane-integrated γ-secretase cleaves βCTF by using γ-secretase associated with lipid rafts. Quantitative analyses using liquid chromatography-tandem mass spectrometry of the βCTF transmembrane domain-derived peptides released along with Aβ generation revealed that the raft-associated γ-secretase cleaves βCTF in a stepwise sequential manner, but novel penta- and hexapeptides as well as tri- and tetrapeptides are released. The cropping of these peptides links the two major tripeptide-cleaving pathways generating Aβ40 and Aβ42 at several points, implying that there are multiple interactive pathways for the stepwise cleavages of βCTF. It should be noted that Aβ38 and Aβ43 are generated through three routes, and γ-secretase modulator 1 enhances all the three routes generating Aβ38, which results in decreases in Aβ42 and Aβ43 and an increase in Aβ38. These observations indicate that multiple interactive pathways for stepwise successive processing by γ-secretase define the species and quantity of Aβ produced.
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