ArticleCell reports2024
Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes.
Article in Cell reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 35 citations in OpenAlex.
- AHA1 Regulates Aβ Production via Modulation of APP Abundance and γ-Secretase Assembly.Journal of neurochemistry · 2026Article
- The γ-secretase complex: from discovery to a therapeutic target.RSC chemical biology · 2026Review
- Kat5 cKO mouse replicates biological domain signatures associated with Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- From mechanistic modeling to AI-driven design: computational strategies for targeting the γ-secretase complex.Briefings in bioinformatics · 2026Review
- A C. elegans model of familial Alzheimer's disease shows age-dependent synaptic degeneration independent of amyloid β-peptide.Neurobiology of disease · 2026Article
- Association of Aβ monomers with cerebral amyloid angiopathy in brains without parenchymal Aβ deposition.Brain communications · 2026Article
- Inhibitory proteins ofJournal of bacteriology · 2025Article
- Structures of CRP antigen-antibody complexes provide insights into the mechanism of specific recognition.Communications biology · 2025Article
- Unraveling the conformational landscape of amyloid precursor protein intracellular domain.Biophysical journal · 2025Article
- Restoring amyloid-β42 and γ-secretase function in Alzheimer's disease.Brain : a journal of neurology · 2025Review
- γ-Secretase-Mediated Endoproteolysis of Neuregulin-1 and E-Cadherin.Biochemistry · 2025Article
- Presenilin-1 Familial Alzheimer Mutations Impair γ-Secretase Cleavage of APP Through Stabilized Enzyme-Substrate Complex Formation.Biomolecules · 2025Article
- Presenilin, γ-Secretase, and the Search for Pathogenic Triggers of Alzheimer's Disease.Biochemistry · 2025Review
- Article
- The Neuroprotective Effect of Rooibos Herbal Tea Against Alzheimer's Disease: A Review.Molecular nutrition & food research · 2025Review
- Pathophysiologic abnormalities in transgenic mice carrying the Alzheimer disease PSEN1 Δ440 mutation.Human molecular genetics · 2024Article
- Alzheimer-mutant γ-secretase complexes stall amyloid β-peptide production.bioRxiv : the preprint server for biology · 2024Article
- Saponin components inFrontiers in pharmacology · 2024Review
- γ-Secretase: once and future drug target for Alzheimer's disease.Expert opinion on drug discoveryArticle
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
Abstract
Mutations that cause familial Alzheimer's disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid β-peptide (Aβ). Nevertheless, whether Aβ is the primary disease driver remains controversial. We report here that FAD mutations disrupt initial proteolytic events in the multistep processing of APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals that a substrate mimetic traps γ-secretase during the transition state, and this structure aligns with activated enzyme-substrate complex captured by molecular dynamics simulations. In silico simulations and in cellulo fluorescence microscopy support stabilization of enzyme-substrate complexes by FAD mutations. Neuronal expression of C99 and/or presenilin-1 in Caenorhabditis elegans leads to synaptic loss only with FAD-mutant transgenes. Designed mutations that stabilize the enzyme-substrate complex and block Aβ production likewise led to synaptic loss. Collectively, these findings implicate the stalled process-not the products-of γ-secretase cleavage of substrates in FAD pathogenesis.
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What Socratic holds
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 Socratic graph.