ArticleEMBO reports2020
Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation.
Article in EMBO reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 32 citations in OpenAlex.
- γ-Secretase modulator resistance of an aggressive Alzheimer-causing presenilin mutant can be overcome in the heterozygous patient state by a set of advanced compounds.Alzheimer's research & therapy · 2025Article
- Aβ43 levels determine the onset of pathological amyloid deposition.The Journal of biological chemistry · 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
- Effects of presenilin-1 familial Alzheimer's disease mutations on γ-secretase activation for cleavage of amyloid precursor protein.Communications biology · 2023Article
- Review
- Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene.International journal of molecular sciences · 2022Review
- An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations.Biophysical journal · 2022Article
- Structure and mechanism of the γ-secretase intramembrane protease complex.Current opinion in structural biology · 2022Review
- Article
- Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice.Acta neuropathologica communications · 2021Article
- [Progress on loss-of-function hypothesis of presenilin-1 mutations in Alzheimer diseases].Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2020Article
- Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature.RSC advances · 2020Article
- Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation.EMBO reports · 2020Article
- Decreased Deposition of Beta-Amyloid 1-38 and Increased Deposition of Beta-Amyloid 1-42 in Brain Tissue of Presenilin-1 E280A Familial Alzheimer's Disease Patients.Frontiers in aging neuroscience · 2020Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 3 countries.
Funding
Abstract
Abnormal generation of neurotoxic amyloid-β peptide (Aβ) 42/43 species due to mutations in the catalytic presenilin 1 (PS1) subunit of γ-secretase is the major cause of familial Alzheimer's disease (FAD). Deeper mechanistic insight on the generation of Aβ43 is still lacking, and it is unclear whether γ-secretase modulators (GSMs) can reduce the levels of this Aβ species. By comparing several types of Aβ43-generating FAD mutants, we observe that very high levels of Aβ43 are often produced when presenilin function is severely impaired. Altered interactions of C99, the precursor of Aβ, are found for all mutants and are independent of their particular effect on Aβ production. Furthermore, unlike previously described GSMs, the novel compound RO7019009 can effectively lower Aβ43 production of all mutants. Finally, substrate-binding competition experiments suggest that RO7019009 acts mechanistically after initial C99 binding. We conclude that altered C99 interactions are a common feature of diverse types of PS1 FAD mutants and that also patients with Aβ43-generating FAD mutations could in principle be treated by GSMs.
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Registered trials
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