ArticleThe journal of physical chemistry. B2013
Familial Alzheimer's disease Osaka mutant (ΔE22) β-barrels suggest an explanation for the different Aβ1-40/42 preferred conformational states observed by experiment.
Article in The journal of physical chemistry. B, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 39 citations in OpenAlex.
- Aggregation-Dependent Epitope Sequence and Modification Fingerprints of Anti-Aβ Antibodies.bioRxiv : the preprint server for biology · 2025Article
- Neurotoxic β-amyloid oligomers cause mitochondrial dysfunction-the trigger for PANoptosis in neurons.Frontiers in aging neuroscience · 2024Review
- Review
- Medin Oligomer Membrane Pore Formation: A Potential Mechanism of Vascular Dysfunction.Biophysical journal · 2020Article
- APP Osaka Mutation in Familial Alzheimer's Disease-Its Discovery, Phenotypes, and Mechanism of Recessive Inheritance.International journal of molecular sciences · 2020Review
- Effect of Post-Translational Modifications and Mutations on Amyloid-β Fibrils Dynamics at N Terminus.Biophysical journal · 2019Article
- Insights into the Molecular Mechanisms of Alzheimer's and Parkinson's Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology.International journal of molecular sciences · 2018Review
- Atomic-resolution map of the interactions between an amyloid inhibitor protein and amyloid β (Aβ) peptides in the monomer and protofibril states.The Journal of biological chemistry · 2017Article
- Graphite-Templated Amyloid Nanostructures Formed by a Potential Pentapeptide Inhibitor for Alzheimer's Disease: A Combined Study of Real-Time Atomic Force Microscopy and Molecular Dynamics Simulations.Langmuir : the ACS journal of surfaces and colloids · 2017Article
- Amyloid β Ion Channels in a Membrane Comprising Brain Total Lipid Extracts.ACS chemical neuroscience · 2017Article
- Reduced Lipid Bilayer Thickness Regulates the Aggregation and Cytotoxicity of Amyloid-β.The Journal of biological chemistry · 2017Article
- The higher level of complexity of K-Ras4B activation at the membrane.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2016Article
- Computational Methods for Structural and Functional Studies of Alzheimer's Amyloid Ion Channels.Methods in molecular biology (Clifton, N.J.) · 2016Article
- Coupling of Zinc-Binding and Secondary Structure in Nonfibrillar Aβ40 Peptide Oligomerization.Journal of chemical information and modeling · 2015Article
- Amyloid β Protein and Alzheimer's Disease: When Computer Simulations Complement Experimental Studies.Chemical reviews · 2015Review
- Mechanisms of membrane binding of small GTPase K-Ras4B farnesylated hypervariable region.The Journal of biological chemistry · 2015Article
- Modulation of Alzheimer's Aβ protofilament-membrane interactions by lipid headgroups.ACS chemical neuroscience · 2015Article
- Article
- Disordered amyloidogenic peptides may insert into the membrane and assemble into common cyclic structural motifs.Chemical Society reviews · 2014Review
- Role of the fast kinetics of pyroglutamate-modified amyloid-β oligomers in membrane binding and membrane permeability.Biochemistry · 2014Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
An unusual ΔE693 mutation in the amyloid precursor protein (APP) producing a β-amyloid (Aβ) peptide lacking glutamic acid at position 22 (Glu22) was recently discovered, and dabbed the Osaka mutant (ΔE22). Previously, several point mutations in the Aβ peptide involving Glu22 substitutions were identified and implicated in the early onset of familial Alzheimer's disease (FAD). Despite the absence of Glu22, the Osaka mutant is also associated with FAD, showing a recessive inheritance in families affected by the disease. To see whether this aggregation-prone Aβ mutant could directly relate to the Aβ ion channel-mediated mechanism as observed for the wild type (WT) Aβ peptide in AD pathology, we modeled Osaka mutant β-barrels in a lipid bilayer. Using molecular dynamics (MD) simulations, two conformer ΔE22 barrels with the U-shaped monomer conformation derived from NMR-based WT Aβ fibrils were simulated in explicit lipid environment. Here, we show that the ΔE22 barrels obtain the lipid-relaxed β-sheet channel topology, indistinguishable from the WT Aβ1-42 barrels, as do the outer and pore dimensions of octadecameric (18-mer) ΔE22 barrels. Although the ΔE22 barrels lose the cationic binding site in the pore which is normally provided by the negatively charged Glu22 side chains, the mutant pores gain a new cationic binding site by Glu11 at the lower bilayer leaflet, and exhibit ion fluctuations similar to the WT barrels. Of particular interest, this deletion mutant suggests that toxic WT Aβ1-42 would preferentially adopt a less C-terminal turn similar to that observed for Aβ17-42, and explains why the solid state NMR data for Aβ1-40 point to a more C-terminal turn conformation. The observed ΔE22 barrels conformational preferences also suggest an explanation for the lower neurotoxicity in rat primary neurons as compared to WT Aβ1-42.
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Registered trials
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