ArticleThe Journal of biological chemistry2014
The Alzheimer disease protective mutation A2T modulates kinetic and thermodynamic properties of amyloid-β (Aβ) aggregation.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 142 citations in OpenAlex.
- Clustering hinders APP α-secretase processing in the plasma membrane.Biophysical journal · 2026Article
- Transmissible long-term neuroprotective and pro-cognitive effects of 1-42 beta-amyloid with A2T icelandic mutation in an Alzheimer's disease mouse model.Molecular psychiatry · 2024Article
- Review
- Can Genetic Markers Predict the Sporadic Form of Alzheimer's Disease? An Updated Review on Genetic Peripheral Markers.International journal of molecular sciences · 2023Review
- Unraveling Molecular and Genetic Insights into Neurodegenerative Diseases: Advances in Understanding Alzheimer's, Parkinson's, and Huntington's Diseases and Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2023Review
- Aβ1-6Molecular psychiatry · 2023Article
- A novel bio-inspired strategy to prevent amyloidogenesis and synaptic damage in Alzheimer's disease.Molecular psychiatry · 2022Article
- Article
- Resolution exchange with tunneling for enhanced sampling of protein landscapes.Physical review. E · 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
- AAV-mediated delivery of an anti-BACE1 VHH alleviates pathology in an Alzheimer's disease model.EMBO molecular medicine · 2022Article
- Effect of Cholesterol Molecules on Aβ1-42 Wild-Type and Mutants Trimers.Molecules (Basel, Switzerland) · 2022Article
- Insertion of the Icelandic Mutation (A673T) by Prime Editing: A Potential Preventive Treatment for Familial and Sporadic Alzheimer's Disease.The CRISPR journal · 2022Article
- BACE1: A Key Regulator in Alzheimer's Disease Progression and Current Development of its Inhibitors.Current neuropharmacology · 2022Review
- Dynamics of Amyloid Formation from Simplified Representation to Atomistic Simulations.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Amyloidogenic Processing of Amyloid Precursor Protein Drives Stretch-Induced Disruption of Axonal Transport in hiPSC-Derived Neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Gene therapy using Aβ variants for amyloid reduction.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Spontaneous Formation of β-sheet Nano-barrels during the Early Aggregation of Alzheimer's Amyloid Beta.Nano today · 2021Article
- Alzheimer's protection effect of A673T mutation may be driven by lower Aβ oligomer binding affinity.Journal of neurochemistry · 2021Article
- Protective genes and pathways in Alzheimer's disease: moving towards precision interventions.Molecular neurodegeneration · 2021Review
16 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Missense mutations in alanine 673 of the amyloid precursor protein (APP), which corresponds to the second alanine of the amyloid β (Aβ) sequence, have dramatic impact on the risk for Alzheimer disease; A2V is causative, and A2T is protective. Assuming a crucial role of amyloid-Aβ in neurodegeneration, we hypothesized that both A2V and A2T mutations cause distinct changes in Aβ properties that may at least partially explain these completely different phenotypes. Using human APP-overexpressing primary neurons, we observed significantly decreased Aβ production in the A2T mutant along with an enhanced Aβ generation in the A2V mutant confirming earlier data from non-neuronal cell lines. More importantly, thioflavin T fluorescence assays revealed that the mutations, while having little effect on Aβ42 peptide aggregation, dramatically change the properties of the Aβ40 pool with A2V accelerating and A2T delaying aggregation of the Aβ peptides. In line with the kinetic data, Aβ A2T demonstrated an increase in the solubility at equilibrium, an effect that was also observed in all mixtures of the A2T mutant with the wild type Aβ40. We propose that in addition to the reduced β-secretase cleavage of APP, the impaired propensity to aggregate may be part of the protective effect conferred by A2T substitution. The interpretation of the protective effect of this mutation is thus much more complicated than proposed previously.
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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.