Depletion of amyloid‐β peptides from solution by sequestration within fibril‐seeded hydrogels

Yau, Wai‐Ming; Tycko, Robert

doi:10.1002/pro.3387

Cited by 7 publications

(5 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although seeded growth can faithfully propagate molecular structures (4,25,29), fibril structures that depend on cofactors in brain tissue may conceivably be altered when seeded growth is performed in a simple aqueous buffer. Cross-seeding between Aβ40 fibrils and Aβ42 fibrils may also complicate the interpretation of seeded structures, although seeding of Aβ40 by Aβ42 fibrils has been shown to be inefficient (12,52). On the other hand, isolation of clean, well-separated fibrils from brain tissue without seeded growth may not be possible in all cases without treatments that select specific structures (i.e., structures that are least prone to self-association or association with other tissue components) or alter the fibril structures by removal of cofactors or by partial dissolution or digestion.…”

Section: Discussionmentioning

confidence: 99%

Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue

Ghosh

Thurber

Yau

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

140

168

View full text Add to dashboard Cite

Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer’s disease (AD). We report the molecular structure of a specific fibril polymorph, formed by 40-residue Aβ peptides (Aβ40), that is derived from cortical tissue of an AD patient by seeded fibril growth. The structure is determined from cryogenic electron microscopy (cryoEM) images, supplemented by mass-per-length (MPL) measurements and solid-state NMR (ssNMR) data. Previous ssNMR studies with multiple AD patients had identified this polymorph as the most prevalent brain-derived Aβ40 fibril polymorph from typical AD patients. The structure, which has 2.8-Å resolution according to standard criteria, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformations and its organization of cross-β subunits. Unique features include twofold screw symmetry about the fibril growth axis, despite an MPL value that indicates three Aβ40 molecules per 4.8-Å β-sheet spacing, a four-layered architecture, and fully extended conformations for molecules in the central two cross-β layers. The cryoEM density, ssNMR data, and MPL data are consistent with β-hairpin conformations for molecules in the outer cross-β layers. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility.

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue

Ghosh

Thurber

Yau

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

140

168

View full text Add to dashboard Cite

show abstract

“…Proteins and their inhibitor complexes were subjected to mass spectrometry, using the Thermo Dionex Ultimate 3000 HPLC system and Thermo MSQ Plus single quadrupole mass spectrometer 63 . Typically, 10 µl of sample at 20 µM concentration, diluted from a reaction mixture in 5% acetic acid, was loaded onto an Acclaim PepMap 300 C4 column (1.0 × 15 cm, Thermo Fisher Scientific) at 40 °C, with 0.2 ml/min flow rates in 2% acetonitrile/95% water/0.01% TFA.…”

Section: Methodsmentioning

confidence: 99%

Autoprocessing and oxyanion loop reorganization upon GC373 and nirmatrelvir binding of monomeric SARS-CoV-2 main protease catalytic domain

et al. 2022

View full text Add to dashboard Cite

The monomeric catalytic domain (residues 1–199) of SARS-CoV-2 main protease (MPro1-199) fused to 25 amino acids of its flanking nsp4 region mediates its autoprocessing at the nsp4-MPro1-199 junction. We report the catalytic activity and the dissociation constants of MPro1-199 and its analogs with the covalent inhibitors GC373 and nirmatrelvir (NMV), and the estimated monomer-dimer equilibrium constants of these complexes. Mass spectrometry indicates the presence of the accumulated adduct of NMV bound to MProWT and MPro1-199 and not of GC373. A room temperature crystal structure reveals a native-like fold of the catalytic domain with an unwound oxyanion loop (E state). In contrast, the structure of a covalent complex of the catalytic domain-GC373 or NMV shows an oxyanion loop conformation (E* state) resembling the full-length mature dimer. These results suggest that the E-E* equilibrium modulates autoprocessing of the main protease when converting from a monomeric polyprotein precursor to the mature dimer.

show abstract

“…Our finding of greater differences on average for A42 fibrils suggests that the distribution of A42 fibril polymorphs in cortical tissue may be more predictive of cognitive impairment than the distribution of A40 fibril polymorphs. It should be recognized that cross-seeding between different A isoforms, as observed in vitro under certain circumstances (60), may affect this finding. If cross-seeding is significant, solid state NMR data for A42 may not reflect only the properties of A42 fibrils in the original tissue.…”

Section: A40 Versus A42mentioning

confidence: 99%

Structural differences in amyloid-β fibrils from brains of nondemented elderly individuals and Alzheimer's disease patients

Ghosh

Yau

Collinge

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Although amyloid plaques composed of fibrillar amyloid-β (Aβ) assemblies are a diagnostic hallmark of Alzheimer's disease (AD), quantities of amyloid similar to those in AD patients are observed in brain tissue of some nondemented elderly individuals. The relationship between amyloid deposition and neurodegeneration in AD has, therefore, been unclear. Here, we use solid-state NMR to investigate whether molecular structures of Aβ fibrils from brain tissue of nondemented elderly individuals with high amyloid loads differ from structures of Aβ fibrils from AD tissue. Two-dimensional solid-state NMR spectra of isotopically labeled Aβ fibrils, prepared by seeded growth from frontal lobe tissue extracts, are similar in the two cases but with statistically significant differences in intensity distributions of cross-peak signals. Differences in solid-state NMR data are greater for 42-residue amyloid-β (Aβ42) fibrils than for 40-residue amyloid-β (Aβ40) fibrils. These data suggest that similar sets of fibril polymorphs develop in nondemented elderly individuals and AD patients but with different relative populations on average.

show abstract

Depletion of amyloid‐β peptides from solution by sequestration within fibril‐seeded hydrogels

Cited by 7 publications

References 71 publications

Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue

Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue

Autoprocessing and oxyanion loop reorganization upon GC373 and nirmatrelvir binding of monomeric SARS-CoV-2 main protease catalytic domain

Structural differences in amyloid-β fibrils from brains of nondemented elderly individuals and Alzheimer's disease patients

Contact Info

Product

Resources

About