ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2005
Familial Alzheimer's disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 154 citations in OpenAlex.
- Pathological calcium influx through amyloid beta pores disrupts synaptic function.Cell calcium · 2025Article
- Role of Mitochondrial Calcium Dysregulation in Alzheimer's Disease Pathogenesis.Molecular neurobiology · 2025Review
- PF-04691502, a PI3K/mTOR Dual Inhibitor, Ameliorates AD-like Pathology in a Mouse Model of AD.Cells · 2025Article
- PS1/gamma-secretase acts as rogue chaperone of glutamate transporter EAAT2/GLT-1 in Alzheimer's disease.Acta neuropathologica communications · 2024Article
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- Familial Alzheimer's Disease Neurons Bearing Mutations inLife (Basel, Switzerland) · 2024Article
- A clathrin mediated endocytosis scaffolding protein, Intersectin 1, changes in an isoform, brain region, and sex specific manner in Alzheimer's disease.Frontiers in neuroscience · 2024Article
- PS1/gamma-secretase acts as rogue chaperone of glutamate transporter EAAT2/GLT-1 in Alzheimer's disease.Research square · 2023Article
- Dysfunctional Glucose Metabolism in Alzheimer's Disease Onset and Potential Pharmacological Interventions.International journal of molecular sciences · 2022Review
- CRISPR-Cas9 treatment partially restores amyloid-β 42/40 in human fibroblasts with the Alzheimer's diseaseMolecular therapy. Nucleic acids · 2022Article
- Alzheimer's disease-causing presenilin-1 mutations have deleterious effects on mitochondrial function.Theranostics · 2021Article
- A Guide to Fluorescence Lifetime Microscopy and Förster's Resonance Energy Transfer in Neuroscience.Current protocols in neuroscience · 2020Review
- Milestones in the development and implementation of FRET-based sensors of intracellular signals: A biological perspective of the history of FRET.Cellular signalling · 2020Review
- Conformational Dynamics of Transmembrane Domain 3 of Presenilin 1 Is Associated with the Trimming Activity of γ-Secretase.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- Synapsin 1 promotes Aβ generation via BACE1 modulation.PloS one · 2019Article
- Article
- Neuronal Ryanodine Receptors in Development and Aging.Molecular neurobiology · 2018Review
- Bidirectional regulation of Aβ levels by Presenilin 1.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Dynamic presenilin 1 and synaptotagmin 1 interaction modulates exocytosis and amyloid β production.Molecular neurodegeneration · 2017Article
- Pathogenic PS1 phosphorylation at Ser367.eLife · 2017Article
12 more citing papers are in PubMed but not listed here.
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7 authors at 1 institution in 1 country.
Funding
Abstract
Presenilin 1 (PS1) is a critical component of the gamma-secretase complex, an enzymatic activity that cleaves amyloid beta (Abeta) from the amyloid precursor protein (APP). More than 100 mutations spread throughout the PS1 molecule are linked to autosomal dominant familial Alzheimer's disease (FAD). All of these mutations lead to a similar phenotype: an increased ratio of Abeta42 to Abeta40, increased plaque deposition, and early age of onset. We use a recently developed microscopy approach, fluorescence lifetime imaging microscopy, to monitor the relative molecular distance between PS1 N and C termini in intact cells. We show that FAD-linked missense mutations located near the N and C termini, in the mid-region of PS1, and the exon 9 deletion mutation all change the spatial relationship between PS1 N and C termini in a similar way, increasing proximity of the two epitopes. This effect is opposite of that observed by treatment with Abeta42-lowering nonsteroidal anti-inflammatory drugs (NSAIDs) (Lleo et al., 2004b). Accordingly, treatment of M146L PS1-overexpressing neurons with high-dose NSAIDs somewhat offsets the conformational change associated with the mutation. Moreover, by monitoring the relative distance between a PS1 loop epitope and the APP C terminus, we demonstrate that the FAD PS1 mutations are also associated with a consistent change in the configuration of the PS1-APP complex. The nonpathogenic E318G PS1 polymorphism had no effect on PS1 N terminus-C terminus proximity or PS1-APP interactions. We propose that the conformational change we observed may therefore provide a shared molecular mechanism for FAD pathogenesis caused by a wide range of PS1 mutations.
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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.