On the lack of polymorphism in Aβ‐peptide aggregates derived from patient brains

Alred, Erik J.; Phillips, Malachi; Berhanu, Workalemahu M.; Hansmann, Ulrich H. E.

doi:10.1002/pro.2668

Cited by 17 publications

(20 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The terminal Aβ chains in AL 3x6 and AL 3x12 lacking a second β-sheet binding partner were more mobile than the other chains, which is known from other simulation studies [38, 47, 57–59]. Overall, our findings for the full-length Aβ40 systems with respect to their structural stability are in agreement with earlier studies [35, 36]. …”

Section: Resultssupporting

confidence: 92%

“…The individual Aβ filaments formed a linear arrangement, showed a strong twisting of the stacks relative to each other, or underwent dissociation of one stack. Three Aβ layers are thus not sufficient to stabilize a triple-fibril conformation in accordance with previous findings [35, 36]. Thus, these systems were excluded from further analysis.…”

Section: Resultssupporting

confidence: 62%

“…Alred et al [35] compared the conformational stability of this fibril to that of a two-fold symmetric Aβ fibril. Other studies investigated the fibril growth mechanism by coarse grained MD simulations [36] or the strength of peptide interactions by quantum chemical methods [37].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Role of the N-terminus for the stability of an amyloid-β fibril with three-fold symmetry

2017

View full text Add to dashboard Cite

A key player in Alzheimer’s disease is the peptide amyloid-beta (Aβ), whose aggregation into small soluble oligomers, protofilaments, and fibrils finally leads to plaque deposits in human brains. The aggregation behavior of Aβ is strongly modulated by the nature and composition of the peptide’s environment and by its primary sequence properties. The N-terminal residues of Aβ play an important role, because they are known to change the peptide’s aggregation propensity. Since these residues are for the first time completely resolved at the molecular level in a three-fold symmetric fibril structure derived from a patient, we chose that system as template for a systematic investigation of the influence of the N-terminus upon structural stability. Using atomistic molecular dynamics simulations, we examined several fibrillar systems comprising three, six, twelve and an infinite number of layers, both with and without the first eight residues. First, we found that three layers are not sufficient to stabilize the respective Aβ topology. Second, we observed a clear stabilizing effect of the N-terminal residues upon the overall fibril fold: truncated Aβ systems were less stable than their full-length counterparts. The N-terminal residues Arg5, Asp7, and Ser8 were found to form important interfilament contacts stabilizing the overall fibril structure of three-fold symmetry. Finally, similar structural rearrangements of the truncated Aβ species in different simulations prompted us to suggest a potential mechanism involved in the formation of amyloid fibrils with three-fold symmetry.

show abstract

Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 62%

See 1 more Smart Citation

Role of the N-terminus for the stability of an amyloid-β fibril with three-fold symmetry

2017

View full text Add to dashboard Cite

show abstract

“…Even though it would contribute to the binding, to make it stronger, this small region, being highly flexible, is expected to have a small favorable free energy contribution. We chose not to use the 2M4J structure of 1–40 Aβ fibril determined from a single patient 69 , since more research into the variability between structures found in patients is needed before using one or the other structure as the most probable structure formed in vivo 69 and, this structure in particular was found to be unstable, by computer simulation 70 . We chose the 2LMQ structure for the fibrils formed in vitro to be the one to characterize the fibrils that we used experimentally to interact with Tat, as they were prepared in the same way.…”

Section: Methodsmentioning

confidence: 99%

HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity

Hategan

Bianchet²,

Steiner

et al. 2017

Nat Struct Mol Biol

View full text Add to dashboard Cite

We investigated direct interactions between the human immunodeficiency virus (HIV)-trans-activator of transcription (Tat) protein and amyloid β peptide. Amyloid β-Tat complexes are readily formed extracellularly in the brain. In vitro studies showed that in the presence of Tat, the uniform amyloid fibrils turned into double twisted fibrils followed by populations with thick unstructured filaments and aggregated large patches in a dose-dependent manner. The fibers became more rigid and mechanically resistant. Tat attached externally to fibrils, causing their lateral aggregation into thick multifibrilar structures. These present growth in β sheet and enhanced adhesion. The neurotoxic properties of Tat and amyloid β aggregates were strongly synergistic when complexed together in vitro and in animal models. These data suggest that the increased rigidity and mechanical resistance of the amyloid β-Tat complexes coupled with stronger adhesion due to the presence of Tat in the fibrils accounted for the increased damage, likely through pore formation in membranes.

show abstract

“…Solid-state NMR experiments distinguished at least three Aβ polymorphic amyloid structures, which were recently analyzed in silico. 54 The two-fold symmetry fibril structure considered here was obtained in vitro under agitated conditions, 4 whereas under in vitro quiescent conditions three-fold symmetry fibrils form. 5 In both structures, Aβ peptides adopt strand-turn-strand folds, in which the NT binding sites (Tyr10, Val12, His14) exist in simular conformations.…”

Section: Fddnp Biomarker Binds To Aβ Fibril At Two Distinct Locationsmentioning

confidence: 99%

Molecular Mechanisms of Alzheimer’s Biomarker FDDNP Binding to Aβ Amyloid Fibril

Parikh

Klimov

2015

J. Phys. Chem. B

View full text Add to dashboard Cite

Using isobaric-isothermal replica exchange molecular dynamics and the all-atom explicit water model, we examined the binding of FDDNP biomarkers to the Aβ amyloid fibril fragment. Our results can be summarized as follows. First, FDDNP ligands bind with high affinity to the Aβ fibril, and the hydrophobic effect together with π-stacking interactions are the dominant factors governing FDDNP binding. In comparison, electrostatic interactions and hydrogen bonding play a minor role. Second, our simulations reveal a strong tendency of bound FDDNP molecules for self-aggregation. Accordingly, about two-thirds of all bound ligands form aggregated clusters of various sizes, and ligand-ligand interactions make considerable contribution to FDDNP binding. Third, FDDNP ligands bind to two distinct sites on the Aβ fibril. Primary binding sites (NT) are located at the N-terminals of Aβ10-40 peptides, whereas secondary ones (CE) occur on the concave fibril edge near fibril channels. The NT sites are characterized by strong hydrophobic and π-stacking interactions, favorable binding entropy resulting from multiple FDDNP binding orientations and propensity for self-aggregation but relatively weak van der Waals interactions. In contrast, the CE sites offer stronger van der Waals binding interactions but weaker hydrophobic and aromatic interactions and less favorable binding entropy. By comparing our data with previous studies, we suggest that the primary binding locations identified by us are likely to occur in other Aβ fibril polymorphic structures. We also show that FDDNP binds via distinct mechanisms to Aβ fibrils and monomers. We argue that FDDNP binds with stronger affinity to benign Aβ monomers than to the fibrils, raising questions about the ability of FDDNP to selectively label amyloid deposits.

show abstract

On the lack of polymorphism in Aβ‐peptide aggregates derived from patient brains

Cited by 17 publications

References 52 publications

Role of the N-terminus for the stability of an amyloid-β fibril with three-fold symmetry

Role of the N-terminus for the stability of an amyloid-β fibril with three-fold symmetry

HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity

Molecular Mechanisms of Alzheimer’s Biomarker FDDNP Binding to Aβ Amyloid Fibril

Contact Info

Product

Resources

About