ArticleCommunications biology2023
Effects of presenilin-1 familial Alzheimer's disease mutations on γ-secretase activation for cleavage of amyloid precursor protein.
Article in Communications biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 26 citations in OpenAlex.
- Neuroinflammatory and molecular pathways in Alzheimer's disease: mechanistic crosstalk and emerging therapeutic opportunities.Inflammopharmacology · 2026Review
- From mechanistic modeling to AI-driven design: computational strategies for targeting the γ-secretase complex.Briefings in bioinformatics · 2026Review
- Presenilin 1 E280A mutation induces dysfunctional astrocytic phenotype in menstrual stromal-derived astrocyte-like cells.Cellular and molecular life sciences : CMLS · 2025Article
- Cannabidiol and Alzheimer Disease: A Comprehensive Review and In Silico Insights Into Molecular Interactions.The European journal of neuroscience · 2025Review
- PF-06447475 Molecule Attenuates the Neuropathology of Familial Alzheimer's and Coexistent Parkinson's Disease Markers in PSEN1 I416T Dopaminergic-like Neurons.Molecules (Basel, Switzerland) · 2025Article
- Impaired hippocampal circuit function underlying memory encoding and consolidation precede robust Aβ deposition in a mouse model of Alzheimer's disease.bioRxiv : the preprint server for biology · 2025Article
- Combination of Epigallocatechin-3-Gallate and Tramiprosate Prevent Accumulation of Intracellular Aβ and Dysfunctional Autophagy-Lysosomal Pathway at Earliest Stage of Transdifferentiation of Mesenchymal Stromal Cells into PSEN1 E280A Cholinergic-like Neurons.International journal of molecular sciences · 2025Article
- Presenilin, γ-Secretase, and the Search for Pathogenic Triggers of Alzheimer's Disease.Biochemistry · 2025Review
- Polyoxometalates bind multiple targets involved in Alzheimer's disease.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2025Article
- The potential link between the development of Alzheimer's disease and osteoporosis.Biogerontology · 2025Review
- Selective Protonation of Catalytic Dyad for γ-Secretase-Mediated Hydrolysis Revealed by Multiscale Simulations.The journal of physical chemistry. B · 2024Article
- Alzheimer's Disease as Type 3 Diabetes: Understanding the Link and Implications.International journal of molecular sciences · 2024Review
- AlzDiscovery: A computational tool to identify Alzheimer's disease-causing missense mutations using protein structure information.Protein science : a publication of the Protein Society · 2024Article
- Rotenone Induces a Neuropathological Phenotype in Cholinergic-like Neurons Resembling Parkinson's Disease Dementia (PDD).Neurotoxicity research · 2024Article
- Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes.Cell reports · 2024Article
- Death-associated protein kinase 1 as a therapeutic target for Alzheimer's disease.Translational neurodegeneration · 2024Review
- Molecular Dynamics Activation of γ-Secretase for Cleavage of the Notch1 Substrate.ACS chemical neuroscience · 2023Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Presenilin-1 (PS1) is the catalytic subunit of γ-secretase which cleaves within the transmembrane domain of over 150 peptide substrates. Dominant missense mutations in PS1 cause early-onset familial Alzheimer's disease (FAD); however, the exact pathogenic mechanism remains unknown. Here we combined Gaussian accelerated molecular dynamics (GaMD) simulations and biochemical experiments to determine the effects of six representative PS1 FAD mutations (P117L, I143T, L166P, G384A, L435F, and L286V) on the enzyme-substrate interactions between γ-secretase and amyloid precursor protein (APP). Biochemical experiments showed that all six PS1 FAD mutations rendered γ-secretase less active for the endoproteolytic (ε) cleavage of APP. Distinct low-energy conformational states were identified from the free energy profiles of wildtype and PS1 FAD-mutant γ-secretase. The P117L and L286V FAD mutants could still sample the "Active" state for substrate cleavage, but with noticeably reduced conformational space compared with the wildtype. The other mutants hardly visited the "Active" state. The PS1 FAD mutants were found to reduce γ-secretase proteolytic activity by hindering APP residue L49 from proper orientation in the active site and/or disrupting the distance between the catalytic aspartates. Therefore, our findings provide mechanistic insights into how PS1 FAD mutations affect structural dynamics and enzyme-substrate interactions of γ-secretase and APP.
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