Cross-Linked Amyloid β-Protein Oligomers: A Missing Link in Alzheimer’s Disease Pathology?

Urbanc, Brigita

doi:10.1021/acs.jpcb.0c07716

Cited by 10 publications

(15 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Nt and NAC domains of each monomer resemble those of the octamers of Figure 8. It appears that oxidation can cause the sole tyrosine residues in some Aβ 61 and amylin 62 oligomers to cross‐link. The only tyrosine in the Nt + NAC domains occur at a position in the middle of S4.…”

Section: Resultsmentioning

confidence: 99%

The amyloid concentric β‐barrel hypothesis: Models of synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels

Durell

H²

2021

Proteins

View full text Add to dashboard Cite

Amyloid beta (Aβ of Alzheimer's disease) and α-synuclein (α-Syn of Parkinson's disease) form large fibrils. Evidence is increasing however that much smaller oligomers are more toxic and that these oligomers can form transmembrane ion channels. We have proposed previously that Aβ42 oligomers, annular protofibrils, and ion channels adopt concentric β-barrel molecular structures. Here we extend that hypothesis to the superfamily of α, β, and γ-synucleins. Our models of numerous synuclein oligomers, annular protofibrils, tubular protofibrils, lipoproteins, and ion channels were developed to be consistent with sizes, shapes, molecular weights, and secondary structures of assemblies as determined by electron microscopy and other studies.The models have the following features: (1) all subunits have identical structures and interactions; (2) they are consistent with conventional β-barrel theory; (3) the distance between walls of adjacent β-barrels is between 0.6 and 1.2 nm; (4) hydrogen bonds, salt bridges, interactions among aromatic side-chains, burial and tight packing of hydrophobic side-chains, and aqueous solvent exposure of hydrophilic side-chains are relatively optimal; and (5) residues that are identical among distantly related homologous proteins cluster in the interior of most oligomers whereas residues that are hypervariable are exposed on protein surfaces. Atomic scale models of some assemblies were developed.

show abstract

Section: Resultsmentioning

confidence: 99%

The amyloid concentric β‐barrel hypothesis: Models of synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels

Durell

H²

2021

Proteins

View full text Add to dashboard Cite

show abstract

“…Aβ homologs comprise a large superfamily present in most vertebrates. Multiple studies indicate that they have a functional role 38,53,54 including antimicrobial activity 55 . We aligned 2500 homologous sequences from mammals through bony fish (Supplement Fig.…”

Section: Resultsmentioning

confidence: 99%

“…They concluded that at least portions of adjacent S1 segments are antiparallel (consistent with some of our models) rather than in-register parallel. Also, Tyr10 side chains can cross-link under oxidizing conditions to form dimers 38 , indicating that they are proximal in some oligomers. (5) There was no experimental evidence that Aβ42 forms β-barrels.…”

Section: Introductionmentioning

confidence: 99%

The amyloid concentric β-barrel hypothesis: Models of amyloid beta 42 oligomers and annular protofibrils

Guy

Kayed

Durell³

2021

Preprint

View full text Add to dashboard Cite

Amyloid beta (Aβ) peptides, a major contributor to Alzheimers disease, occur in differing lengths, each of which forms a multitude of assembly types. The most toxic soluble oligomers are formed by Aβ42; some of which have antiparallel β-sheets. Previously, our group proposed molecular models of Aβ42 hexamers in which the C-terminus third of the peptide (S3) forms an antiparallel 6-stranded β-barrel that is surrounded by an antiparallel barrel formed by the more polar N-terminus (S1) and middle (S2) portions. These hexamers were proposed to act as seeds from which dodecamers, octadecamers, both smooth and beaded annular protofibrils, and transmembrane channels form. Since then, numerous aspects of our models have been supported by experimental findings. Recently, NMR-based structures have been proposed for Aβ42 tetramers and octamers, and NMR studies have been reported for oligomers composed of ~ 32 monomers. Here we propose a range of concentric β-barrel models and compare their dimensions to image-averaged electron micrographs of both beaded annular protofibrils (bAPFs) and smooth annular protofibrils (sAPFs) of Aβ42. The smaller oligomers have 6, 8, 12, 16, and 18 monomers. These beads string together to form necklace-like bAPFs. These gradually morph into sAPFs in which a S3 β-barrel is shielded on one or both sides by β-barrels formed from S1 and S2 segments.

show abstract

“…They concluded that at least portions of adjacent S1 segments are antiparallel (consistent with some of our models) rather than in‐register parallel. Also, Tyr10 side chains can cross‐link under oxidizing conditions to form dimers, 25 indicating that they are proximal in some oligomers as they are in some of our models. (5) There was no experimental evidence that Aβ42 forms β‐barrels.…”

Section: Introductionmentioning

confidence: 83%

“…Aβ homologs comprise a large superfamily present in most vertebrates. Multiple studies indicate that they have a functional role [23][24][25] including antimicrobial activity. 26 We aligned 250 homologous sequences from all types of vertebrates, mammals through bony fish (Figure S1), to determine which residues are most essential.…”

mentioning

confidence: 99%

The amyloid concentric β‐barrel hypothesis: Models of amyloid beta 42 oligomers and annular protofibrils

Durell

Kayed

H³

2022

Proteins

View full text Add to dashboard Cite

Amyloid beta (Aβ) peptides are a major contributor to Alzheimer's disease. They occur in differing lengths, each of which forms a multitude of assembly types. The most toxic soluble oligomers are formed by Aβ42; some of which have antiparallel β‐sheets. Previously, our group proposed molecular models of Aβ42 hexamers in which the C‐terminus third of the peptide (S3) forms an antiparallel 6‐stranded β‐barrel that is surrounded by an antiparallel barrel formed by the more polar N‐terminus (S1) and middle (S2) portions. These hexamers were proposed to act as seeds from which dodecamers, octadecamers, both smooth annular protofibrils (sAPFs) and beaded annular protofibrils (bAPFs), and transmembrane channels form. Since then, numerous aspects of our models have been supported by experimental findings. Recently, NMR‐based structures have been proposed for Aβ42 tetramers and octamers, and NMR studies have been reported for oligomers composed of ~32 monomers. Here we propose a range of concentric β‐barrel models and compare their dimensions to image‐averaged electron micrographs of both bAPFs and sAPFs of Aβ42. The smaller oligomers have 6, 8, 12, 16, and 18 monomers. These beads string together to form necklace‐like bAPFs. These bAPRs gradually morph into sAPFs in which a S3 β‐barrel is shielded on one or both sides by β‐barrels formed from S1 and S2 segments.

show abstract

Cross-Linked Amyloid β-Protein Oligomers: A Missing Link in Alzheimer’s Disease Pathology?

Cited by 10 publications

References 89 publications

The amyloid concentric β‐barrel hypothesis: Models of synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels

The amyloid concentric β‐barrel hypothesis: Models of synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels

The amyloid concentric β-barrel hypothesis: Models of amyloid beta 42 oligomers and annular protofibrils

The amyloid concentric β‐barrel hypothesis: Models of amyloid beta 42 oligomers and annular protofibrils

Contact Info

Product

Resources

About