ArticleCell discovery2016
Alzheimer's disease-associated mutations increase amyloid precursor protein resistance to γ-secretase cleavage and the Aβ42/Aβ40 ratio.
Article in Cell discovery, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 81 citations in OpenAlex.
- AHA1 Regulates Aβ Production via Modulation of APP Abundance and γ-Secretase Assembly.Journal of neurochemistry · 2026Article
- Conformational Flexibility of Transmembrane Helices: How it Works and Where it Matters.Chemical reviews · 2026Review
- Alzheimer's Disease: From Molecular Pathogenesis to Disease-Modifying Therapies and Clinical Implementation in Aging Populations.Clinical interventions in aging · 2026Review
- The Role of Neprilysin and Insulin-Degrading Enzyme in the Etiology of Sporadic Alzheimer's Disease.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- An approach to predict and inhibit Amyloid Beta dimerization pattern in Alzheimer's disease.Toxicology reports · 2025Article
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- CRISPR/Cas9-Based therapeutics as a promising strategy for management of Alzheimer's disease: progress and prospects.Frontiers in cellular neuroscience · 2025Review
- Simple improvements in vector design afford substantial gains in AAV delivery of aggregation-slowing Aβ variants.Molecular therapy. Nucleic acids · 2024Article
- Towards a Unitary Hypothesis of Alzheimer's Disease Pathogenesis.Journal of Alzheimer's disease : JAD · 2024Article
- Cooperation of N- and C-terminal substrate transmembrane domain segments in intramembrane proteolysis by γ-secretase.Communications biology · 2023Article
- Formation of extramembraneProceedings of the National Academy of Sciences of the United States of America · 2022Article
- CRISPR/Cas9 gene editing: New hope for Alzheimer's disease therapeutics.Journal of advanced research · 2022Review
- A thermodynamic investigation of amyloid precursor protein processing by human γ-secretase.Communications biology · 2022Article
- An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations.Biophysical journal · 2022Article
- Exploring the Involvement of the Amyloid Precursor Protein A673T Mutation against Amyloid Pathology and Alzheimer's Disease in Relation to Therapeutic Editing Tools.Pharmaceutics · 2022Review
- Alzheimer's Disease: A Molecular View of β-Amyloid Induced Morbific Events.Biomedicines · 2021Review
- Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer's Disease, Parkinson's Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis.Chemical reviews · 2021Review
- Can Anti-β-amyloid Monoclonal Antibodies Work in Autosomal Dominant Alzheimer Disease?Neurology. Genetics · 2021Review
- Anti-Parallel β-Hairpin Structure in Soluble Aβ Oligomers of Aβ40-Dutch and Aβ40-Iowa.International journal of molecular sciences · 2021Article
- The Links between Cardiovascular Diseases and Alzheimer's Disease.Current neuropharmacology · 2021Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Mutations in the amyloid precursor protein (APP) gene and the aberrant cleavage of APP by γ-secretase are associated with Alzheimer's disease (AD). Here we have developed a simple and sensitive cell-based assay to detect APP cleavage by γ-secretase. Unexpectedly, most familial AD (FAD)-linked APP mutations make APP partially resistant to γ-secretase. Mutations that alter residues N terminal to the γ-secretase cleavage site Aβ42 have subtle effects on cleavage efficiency and cleavage-site selectivity. In contrast, mutations that alter residues C terminal to the Aβ42 site reduce cleavage efficiency and dramatically shift cleavage-site specificity toward the aggregation-prone Aβ42. Moreover, mutations that remove positive charge at residue 53 greatly reduce the APP cleavage by γ-secretase. These results suggest a model of γ-secretase substrate recognition, in which the APP region C terminal to the Aβ42 site and the positively charged residue at position 53 are the primary determinants for substrate binding and cleavage-site selectivity. We further demonstrate that this model can be extended to γ-secretase processing of notch receptors, a family of highly conserved cell-surface signaling proteins.
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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.