Stability of Amyloid Oligomers

Berhanu, Workalemahu M.; Hansmann, Ulrich H. E.

doi:10.1016/bs.apcsb.2014.06.006

Cited by 21 publications

(23 citation statements)

References 183 publications

(213 reference statements)

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“…The strong interest in oligomeric species is also supported by the need for new therapeutic or diagnostic targets.Alarge number of reviews on amyloid oligomers have recently been published. [12][13][14][15][16][17][18][19][20] They focus either on single proteins or peptides as associated with one type of disease or on differenta spects of the oligomeric structures in the context of amyloid formation in general. Of special interest, for instance, is the impact of bound metal ions on the self-assembly of amyloid proteins.…”

Section: Introductionmentioning

confidence: 99%

An Account of Amyloid Oligomers: Facts and Figures Obtained from Experiments and Simulations

2016

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The deposition of amyloid in brain tissue in the context of neurodegenerative diseases involves the formation of intermediate species-termed oligomers-of lower molecular mass and with structures that deviate from those of mature amyloid fibrils. Because these oligomers are thought to be primarily responsible for the subsequent disease pathogenesis, the elucidation of their structure is of enormous interest. Nevertheless, because of the high aggregation propensity and the polydispersity of oligomeric species formed by the proteins or peptides in question, the preparation of appropriate samples for high-resolution structural methods has proven to be rather difficult. This is why theoretical approaches have been of particular importance in gaining insights into possible oligomeric structures for some time. Only recently has it been possible to achieve some progress with regard to the experimentally based structural characterization of defined oligomeric species. Here we discuss how theory and experiment are used to determine oligomer structures and what can be done to improve the integration of the two disciplines.

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Section: Introductionmentioning

confidence: 99%

An Account of Amyloid Oligomers: Facts and Figures Obtained from Experiments and Simulations

2016

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“…The later suffer from the problem that aggregation, and conversions between different forms of aggregates, takes hours or longer, that is happens on time scales that are not accessible in molecular dynamic simulations. 5,6 For this reason, we address the above question by comparing the stability of structurally distinct Ab amyloid fibrils in atomistic molecular dynamics simulations with explicit solvent. Specifically, we study a two-fold in vitro model of Ab fibrils (PDB code: 2LMO), a three-fold in vitro model (PDB code: 2LMP), and the three-fold in vivo (patient-derived) model (PDB code: 2M4J).…”

Section: Introductionmentioning

confidence: 99%

“…While faster than direct aggregation simulations, such stability investigations are still computationally taxing, and often the temperature is raised to increase sampling speed. 5,7 In the present paper, we use a different approach, reducing the viscosity of the system through mass scaling. Long-time all-atom explicit solvent molecular simulations are performed of in vitro and in vivo Ab fibril models of various arrangements and sizes.…”

Section: Introductionmentioning

confidence: 99%

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

Alred

Phillips²,

Berhanu³

et al. 2015

Protein Science

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The amyloid beta (Ab) oligomers and fibrils that are found in neural tissues of patients suffering from Alzheimer's disease may either cause or contribute to the pathology of the disease. In vitro, these Ab-aggregates are characterized by structural polymorphism. However, recent solid state NMR data of fibrils acquired post mortem from the brains of two Alzheimer's patients indicate presence of only a single, patient-specific structure. Using enhanced molecular dynamic simulations we investigate the factors that modulate the stability of Ab-fibrils. We find characteristic differences in molecular flexibility, dynamics of interactions, and structural behavior between the brain-derived Ab-fibril structure and in vitro models. These differences may help to explain the lack of polymorphism in fibrils collected from patient brains, and have to be taken into account when designing aggregation inhibitors and imaging agents for Alzheimer's disease.

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“…Manipulation of aoTTR resulted in the emergence of intermediates whose mechanical transitions occurred at higher force values than those observed in nTTR (Figure D). This difference could be interpreted because of amyloid oligomers typically attain a more stable state than the native protein from which they are derived . However, such interpretation should be viewed with some caution.…”

Section: Discussionmentioning

confidence: 99%

“…This difference could be interpreted because of amyloid oligomers typically attain a more stable state than the native protein from which they are derived. [53][54][55][56][57][58][59][60][61] However, such interpretation should be viewed with some caution.…”

Section: Unfolding Force Of Intermediatesmentioning

confidence: 99%

Force spectroscopy reveals the presence of structurally modified dimers in transthyretin amyloid annular oligomers

Pires

Saraiva

Damas

et al. 2016

J of Molecular Recognition

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Toxicity in amyloidogenic protein misfolding disorders is thought to involve intermediate states of aggregation associated with the formation of amyloid fibrils. Despite their relevance, the heterogeneity and transience of these oligomers have placed great barriers in our understanding of their structural properties. Among amyloid intermediates, annular oligomers or annular protofibrils have raised considerable interest because they may contribute to a mechanism of cellular toxicity via membrane permeation. Here we investigated, by using AFM force spectroscopy, the structural detail of amyloid annular oligomers from transthyretin (TTR), a protein involved in systemic and neurodegenerative amyloidogenic disorders. Manipulation was performed in situ, in the absence of molecular handles and using persistence length-fit values to select relevant curves. Force curves reveal the presence of dimers in TTR annular oligomers that unfold via a series of structural intermediates. This is in contrast with the manipulation of native TTR that was more often manipulated over length scales compatible with a TTR monomer and without unfolding intermediates. Imaging and force spectroscopy data suggest that dimers are formed by the assembly of monomers in a head-to-head orientation with a nonnative interface along their β-strands. Furthermore, these dimers stack through nonnative contacts that may enhance the stability of the misfolded structure.

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Stability of Amyloid Oligomers

Cited by 21 publications

References 183 publications

An Account of Amyloid Oligomers: Facts and Figures Obtained from Experiments and Simulations

An Account of Amyloid Oligomers: Facts and Figures Obtained from Experiments and Simulations

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

Force spectroscopy reveals the presence of structurally modified dimers in transthyretin amyloid annular oligomers

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