ArticleScientific reports2018
APLP1 is endoproteolytically cleaved by γ-secretase without previous ectodomain shedding.
Article in Scientific reports, 2018. 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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Who cites it
16 citing papers in PubMed, 38 citations in OpenAlex.
- Analysis of Specific Serum Markers for Early Prediction of Alzheimer's Disease in Adolescents with Down Syndrome.Indian journal of clinical biochemistry : IJCB · 2025Article
- Blood-derived APLP1Science advances · 2025Article
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- Comprehensive characterization of the neurogenic and neuroprotective action of a novel TrkB agonist using mouse and human stem cell models of Alzheimer's disease.Stem cell research & therapy · 2024Article
- System-wide vitreous proteome dissection reveals impaired sheddase activity in diabetic retinopathy.Theranostics · 2022Article
- The evolved divergence of γ-secretase-susceptibility of homologous proteins Ngfrb and Nradd in zebrafish.BMC research notes · 2021Article
- Rapid evolution of mammalian APLP1 as a synaptic adhesion molecule.Scientific reports · 2021Article
- Multimodal analysis for humaniScience · 2021Article
- G-749 Promotes Receptor Tyrosine Kinase TYRO3 Degradation and Induces Apoptosis in Both Colon Cancer Cell Lines and Xenograft Mouse Models.Frontiers in pharmacology · 2021Article
- Non-canonical Shedding of TNFα by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix.iScience · 2020Article
- Matriptase processing of APLP1 ectodomain alters its homodimerization.Scientific reports · 2020Article
- A comprehensive systematic review of CSF proteins and peptides that define Alzheimer's disease.Clinical proteomics · 2020Review
- Review
- Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments.The EMBO journal · 2018Review
- Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer's Disease.Frontiers in neuroscience · 2018Article
- Spatiotemporal processing of neural cell adhesion molecules 1 and 2 by BACE1 in vivo.The Journal of biological chemistryArticle
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Authors and funding
6 authors at 5 institutions in 2 countries.
Funding
Abstract
Regulated intramembrane proteolysis of the amyloid precursor protein (APP) and its homologs, the APP like proteins APLP1 and APLP2, is typically a two-step process, which is initiated by ectodomain-shedding of the substrates by α- or β-secretases. Growing evidence, however, indicates that the cleavage process for APLP1 is different than for APP. Here, we describe that full-length APLP1, but not APP or APLP2, is uniquely cleaved by γ-secretase without previous ectodomain shedding. The new fragment, termed sAPLP1γ, was exclusively associated with APLP1, not APP, APLP2. We provide an exact molecular analysis showing that sAPLP1γ was uniquely generated by γ-secretase from full-length APLP1. Mass spectrometry analysis showed that the sAPLP1γ fragment and the longest Aβ-like peptide share the C-terminus. This novel mechanism of γ-secretase action is consistent with an ϵ-cut based upon the nature of the reaction in APP. We further demonstrate that the APLP1 transmembrane sequence is the critical determinant for γ-shedding and release of full-length APLP1. Moreover, the APLP1 TMS is sufficient to convert larger type-I membrane proteins like APP into direct γ-secretase substrates. Taken together, the direct cleavage of APLP1 is a novel feature of the γ-secretase prompting a re-thinking of γ-secretase activity modulation as a therapeutic strategy for Alzheimer disease.
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