scholarly journals Compact fibril-like structure of amyloid β-peptide (1–42) monomers

2021 ◽  
Author(s):  
Bogdan Barz ◽  
Alexander K. Buell ◽  
Soumav Nath
Keyword(s):  
Amyloid Β ◽  
Random Coil ◽  
Amyloid Β Peptide

Amyloid β (Aβ) monomers sample a random-coil type of conformation in water with a tendency to adopt compact structures with fibril-like features.

scholarly journals Monomeric amyloid β-peptide (1-42) significantly populates compact fibril-like conformations

2020 ◽  
Author(s):  
Bogdan Barz ◽  
Alexander K. Buell ◽  
Soumav Nath
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Random Coil ◽  
Amyloid Β Peptide ◽  
Secondary Nucleation ◽  
Fibril Structure ◽  
Amyloid Fibril Formation ◽  
Dynamics Simulations ◽  
The Individual ◽  
Structural Ensemble

AbstractThe aggregation of the amyloid β (Aβ) peptide is a major hallmark of Alzheimer’s disease. This peptide can aggregate into oligomers, proto-fibrils, and mature fibrils, which eventually assemble into amyloid plaques. The peptide monomers are the smallest assembly units, and play an important role in most of the individual processes involved in amyloid fibril formation, such as primary and secondary nucleation and elongation. The structure of the Aβ monomer has been shown to be very dynamic and mostly disordered, both in experimental and in computational studies, similar to a random coil. This structural state of the monomer contrasts with the very stable and well defined structural core of the amyloid fibrils. An important question is whether the monomer can adopt transient fibril-like conformations in solution and what role such conformations might play in the aggregation process. Here we use enhanced and extensive molecular dynamics simulations to study the Aβ42 monomer structural flexibility with different force fields, water models and salt concentrations. We show that the monomer behaves as a random coil under different simulation conditions. Importantly, we find a conformation with the N-terminal region structured very similarly to that of recent experimentally determined fibril models. This is to the best of our knowledge the first monomeric structural ensemble to show such a similarity with the fibril structure.

scholarly journals Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

2021 ◽  
Vol 118 (39) ◽  
pp. e2106210118
Author(s):  
Hebah Fatafta ◽  
Mohammed Khaled ◽  
Michael C. Owen ◽  
Abdallah Sayyed-Ahmad ◽  
Birgit Strodel
Keyword(s):  
Aqueous Phase ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Random Coil ◽  
Neuronal Membrane ◽  
Amyloid Β Peptide ◽  
Main Site ◽  
Neuronal Membranes ◽  
Β Sheet

Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity of amyloid-β peptides in Alzheimer’s disease. To gain a detailed understanding of the mutual interference of amyloid-β oligomers and the neuronal membrane, we carried out microseconds of all-atom molecular dynamics (MD) simulations on the dimerization of amyloid-β (Aβ)42 in the aqueous phase and in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. The dimerization in solution is characterized by a random coil to β-sheet transition that seems on pathway to amyloid aggregation, while the interactions with the neuronal membrane decrease the order of the Aβ42 dimer by attenuating its propensity to form a β-sheet structure. The main lipid interaction partners of Aβ42 are the surface-exposed sugar groups of the gangliosides GM1. As the neurotoxic activity of amyloid oligomers increases with oligomer order, these results suggest that GM1 is neuroprotective against Aβ-mediated toxicity.

scholarly journals Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

2021 ◽  
Author(s):  
Hebah Fatafta ◽  
Mohammed Khaled ◽  
Abdallah Sayyed-Ahmad ◽  
Birgit Strodel
Keyword(s):  
Aqueous Phase ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Md Simulations ◽  
Random Coil ◽  
Neuronal Membrane ◽  
Amyloid Β Peptide ◽  
Neuronal Membranes ◽  
Amyloid Oligomers ◽  
Β Sheet

The aggregation of amyloid β-peptides into neurotoxic oligomers is a key feature in the development of Alzheimer's disease. Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity. To gain a detailed understanding of the mutual effects of amyloid-β oligomers and the neuronal membrane, we carried out a total of 12 μs all-atom molecular dynamics (MD) simulations of the dimerization of the full-length Aβ42 peptide in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. The conformational changes of Aβ42 resulting from its dimerization and interactions with the neuronal membrane are compared to those occurring upon its dimerization in the aqueous phase, which is also tested by 12 μs of MD simulations. We find that the interactions with the neuronal membrane decrease the order of the Aβ42 dimer by attenuating its propensity to form a β-sheet structure. The main lipid interaction partners of Aβ42 are the surface-exposed sugar groups of the gangliosides GM1. Aβ42 dimerization in solution, on the other hand, is characterized by a random coil to β-sheet transition that seems to be on-pathway to amyloid aggregation. As the neurotoxic activity of amyloid oligomers increases with oligomer order, the results suggest that GM1 is neuroprotective against Aβ-mediated toxicity by inhibiting the formation of ordered amyloid oligomers.

scholarly journals Binding of amyloid β-peptide to ganglioside micelles is dependent on histidine-13

2006 ◽  
Vol 397 (3) ◽  
pp. 483-490 ◽  
Author(s):  
Mike P. Williamson ◽  
Yu Suzuki ◽  
Nathan T. Bourne ◽  
Tetsuo Asakura
Keyword(s):  
Conformational Change ◽  
Conformational Changes ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Sialic Acid Residue ◽  
Terminal Region ◽  
Random Coil ◽  
Neuronal Membrane ◽  
Amyloid Β Peptide ◽  
Surface Binding

Amyloid β-peptide (Aβ) is a major component of plaques in Alzheimer's disease, and formation of senile plaques has been suggested to originate from regions of neuronal membrane rich in gangliosides. Here we demonstrate using NMR on 15N-labelled Aβ-(1–40) and Aβ-(1–42) that the interaction with ganglioside GM1 micelles is localized to the N-terminal region of the peptide, particularly residues His13 to Leu17, which become more helical when bound. The key interaction is with His13, which undergoes a GM1-specific conformational change. The sialic acid residue of the ganglioside headgroup is important for determining the nature of the conformational change. The isolated pentasaccharide headgroup of GM1 is not bound, suggesting the need for a polyanionic surface. Binding to heparin confirms this suggestion, since binding is of similar affinity but does not produce the same conformational changes in the peptide. A comparison of Aβ-(1–40) and Aβ-(1–42) indicates that binding to GM1 micelles is not related to oligomerization, which occurs at the C-terminal end. These results imply that binding to ganglioside micelles causes a transition from random coil to α-helix in the N-terminal region, leaving the C-terminal region unstructured.

scholarly journals The conformation of Alzheimer's β peptide determines the rate of amyloid formation and its resistance to proteolysis

1996 ◽  
Vol 314 (2) ◽  
pp. 701-707 ◽  
Author(s):  
Claudio SOTO ◽  
Eduardo M. CASTAÑO
Keyword(s):  
Amino Acid ◽  
Amyloid Β ◽  
Random Coil ◽  
Soluble Form ◽  
Amino Acid Substitutions ◽  
Amyloid Β Peptide ◽  
Amyloid Formation ◽  
Poorly Soluble ◽  
High Concentrations

Amyloid β-peptide (Aβ) is found in an aggregated poorly soluble form in senile or neuritic plaques deposited in the brain of individuals affected by Alzheimer's disease (AD). In addition soluble Aβ (sAβ) is identified normally circulating in human body fluids. In this study we report that synthetic peptides containing the sequences 1–40 and 1–42 of Aβ, and Aβ analogues bearing amino acid substitutions can adopt two major conformational states in solution: (1) an amyloidogenic conformer (Aβac) with a high content of β-sheet and partly resistant to proteases and (2) a non-amyloidogenic conformer (Aβnac) with a random coil conformation and protease-sensitive. The differences in the fibrillogenesis rate and in the protease resistance among the several Aβ peptides studied depend mainly on the relative propensity for adopting the amyloidogenic conformation, which in the absence of external factors is largely conditioned by the primary structure of the peptide. Aβnac containing the sequence 1–40, 1–42 or bearing amino acid substitutions (Dutch variant of Aβ) was protease-sensitive and unable to form a significant amount of amyloid even at high concentrations or after long incubations. The finding of the simultaneous existence of different Aβ conformers with distinct abilities to form amyloid may help to explain why Aβ is found in both soluble and fibrillar forms in vivo.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Insights into amyloid disease from fly models

2014 ◽  
Vol 56 ◽  
pp. 69-83 ◽  
Author(s):  
Ko-Fan Chen ◽  
Damian C. Crowther
Keyword(s):  
Drosophila Melanogaster ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Disease Pathogenesis ◽  
Amyloid Aggregates ◽  
Aβ Amyloid ◽  
Polypeptide Chains ◽  
Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

Analytical methods to explore Amyloid-β-Peptide variants beyond Aβ1-40 and Aβ1-42

2015 ◽  
Vol 48 (06) ◽  
Author(s):  
H Esselmann ◽  
C Hafermann ◽  
O Jahn ◽  
I Kraus ◽  
J Vogelgsang ◽  
...  
Keyword(s):  
Analytical Methods ◽  
Amyloid Β ◽  
Amyloid Β Peptide
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