Alzheimer's Aβ40 Studied by NMR at Low pH Reveals That Sodium 4,4-Dimethyl-4-silapentane-1-sulfonate (DSS) Binds and Promotes β-Ball Oligomerization

Laurents, Douglas V.; Gorman, Paul M.; Guo, Meng; Rico, Manuel; Chakrabartty, Avijit; Bruix, Marta

doi:10.1074/jbc.m409507200

Cited by 36 publications

(33 citation statements)

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“…[8,9,36] Models representing several possible structures of aggregated forms have been proposed very recently. These range in size from dimers to 200-mer spherical b-balls; [13] but aggregation of helical peptides is a widespread mechanism-from antibiotic peptides to virus fusion peptides-that leads to membrane poration.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the natural abundance of 13 C, 13 C-HSQC experiments were also acquired with the samples in the HFIP/H 2 O mixtures with a ratio 30:70 and 80:20. Experiments were collected in phase-sensitive mode [45,46] by using water gradient suppression.…”

Section: Methodsmentioning

confidence: 99%

“…[9,11,12] Recently, different structures of aggregated forms, the so-called b-balls, have also been proposed. [13] Irrespective of the details of each mechanism, most views on neurotoxicity evidence a critical role for in vivo conformational transitions between soluble a helical and b forms of the peptide. Direct observation of such conformational transitions is difficult since all Ab peptides have little tendency to dissolve in water.…”

Section: Introductionmentioning

confidence: 99%

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The α‐to‐β Conformational Transition of Alzheimer's Aβ‐(1–42) Peptide in Aqueous Media is Reversible: A Step by Step Conformational Analysis Suggests the Location of β Conformation Seeding

et al. 2006

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Current views of the role of beta-amyloid (Abeta) peptide fibrils range from regarding them as the cause of Alzheimer's pathology to having a protective function. In the last few years, it has also been suggested that soluble oligomers might be the most important toxic species. In all cases, the study of the conformational properties of Abeta peptides in soluble form constitutes a basic approach to the design of molecules with "antiamyloid" activity. We have experimentally investigated the conformational path that can lead the Abeta-(1-42) peptide from the native state, which is represented by an alpha helix embedded in the membrane, to the final state in the amyloid fibrils, which is characterized by beta-sheet structures. The conformational steps were monitored by using CD and NMR spectroscopy in media of varying polarities. This was achieved by changing the composition of water and hexafluoroisopropanol (HFIP). In the presence of HFIP, beta conformations can be observed in solutions that have very high water content (up to 99 % water; v/v). These can be turned back to alpha helices simply by adding the appropriate amount of HFIP. The transition of Abeta-(1-42) from alpha to beta conformations occurs when the amount of water is higher than 80 % (v/v). The NMR structure solved in HFIP/H2O with high water content showed that, on going from very apolar to polar environments, the long N-terminal helix is essentially retained, whereas the shorter C-terminal helix is lost. The complete conformational path was investigated in detail with the aid of molecular-dynamics simulations in explicit solvent, which led to the localization of residues that might seed beta conformations. The structures obtained might help to find regions that are more affected by environmental conditions in vivo. This could in turn aid the design of molecules able to inhibit fibril deposition or revert oligomerization processes.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The α‐to‐β Conformational Transition of Alzheimer's Aβ‐(1–42) Peptide in Aqueous Media is Reversible: A Step by Step Conformational Analysis Suggests the Location of β Conformation Seeding

et al. 2006

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“…To further understand the link between folding and aggregation in A␤, we probed the structural features of residues around 24-28. Solution NMR data of A␤ and A␤(1-42) suggested turn-like structures in residues 20-26 (4) or a turn in residues 22-25 (27). Solution NMR data of A␤(10-35) (24) and A␤(21-30) (28) indicated a double turn in residues 22-27 and 24-28, respectively.…”

mentioning

confidence: 99%

“…Whereas an intramolecular salt bridge between Asp-23 and Lys-28 was proposed for the fibrils of A␤(1-40) (20), the same salt bridge was suggested to be intermolecular in the fibrils of A␤(1-42) (21). The stability of the turn (24)(25)(26)(27) in A␤(10-35) and the turn (24)(25)(26)(27)(28) in A␤(21-30) has previously been tested in simulation studies (29,30) using the respective NMR structure models (24,28). The simulation study of A␤(21-30) also revealed a salt bridge between Glu-22 and Lys-28 (30).…”

mentioning

confidence: 99%

Linking folding with aggregation in Alzheimer's β-amyloid peptides

Khandogin

Brooks²

2007

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

148

202

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Growing evidence suggests that the ␤-amyloid (A␤) peptides of Alzheimer's disease are generated in early endosomes and that small oligomers are the principal toxic species. We sought to understand whether and how the solution pH, which is more acidic in endosomes than the extracellular environment, affects the conformational processes of A␤. Using constant pH molecular dynamics simulations of two model peptides, A␤(1-28) and A␤(10 -42), we found that the folding landscape of A␤ is strongly modulated by pH and is most favorable for hydrophobically driven aggregation at pH 6. Thus, our theoretical findings substantiate the possibility that A␤ oligomers develop intracellularly before secretion into the extracellular milieu, where they may disrupt synaptic activity or act as seeds for plaque formation.␤-turn ͉ helix ͉ pH-dependent ͉ molecular dynamics ͉ electrostatics P rotein aggregation and fibril formation have been implicated in a number of human diseases, including amyloidoses and neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) that are most prevalent in aged populations. Although it is now widely known that the initial aggregation step for globular proteins involves the formation of a partially unfolded monomeric intermediate (1), little is understood for natively unfolded proteins such as the ␤-amyloid (A␤) peptides of AD and the ␣-synuclein protein of PD. To elucidate the conformational behavior of A␤, fragments as well as the full-length (40 or 42 residues) monomers have been intensively studied by spectroscopic techniques such as circular dichroism (CD) and solution NMR in both water and aqueous solutions of TFE, a cosolvent known to stabilize local hydrogen bonding in peptides with intrinsic helix propensity (2). In water, A␤ peptides have been characterized as mainly unfolded (3, 4) whereas in TFE solution, they display a pH-dependent helix profile with a minimum helix content centered around pH 5.5 (3). An early study showed that A␤(1-28) forms mature fibrils only in the pH range between 3 and 8 (5). A recent kinetics experiment revealed that the full-length A␤ aggregates most rapidly at pH 4-5.7 (6). However, conformational transitions in the early aggregation step as well as its relationship to pH remain unknown. Understanding the role of environmental conditions such as solution pH in the oligomerization of A␤ is important, because increasing experimental data suggest that A␤ is cleaved from the amyloid precursor protein in early endosomes, which have a pH of Ϸ6 (7,8) and that dimers and trimers are necessary and sufficient to disrupt synaptic activity (9, 10).We have recently developed the continuous constant pH molecular dynamics (CPHMD) method (11, 12), which allows conformational dynamics to be microscopically coupled with protonation equilibria in the atomic-level simulation of biological macromolecules. Combined with a state-of-the-art conformational sampling protocol, the replica-exchange (REX) algorithm (13), and an improved continuum solvent model (1...

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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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Alzheimer's Aβ40 Studied by NMR at Low pH Reveals That Sodium 4,4-Dimethyl-4-silapentane-1-sulfonate (DSS) Binds and Promotes β-Ball Oligomerization

Cited by 36 publications

References 60 publications

The α‐to‐β Conformational Transition of Alzheimer's Aβ‐(1–42) Peptide in Aqueous Media is Reversible: A Step by Step Conformational Analysis Suggests the Location of β Conformation Seeding

The α‐to‐β Conformational Transition of Alzheimer's Aβ‐(1–42) Peptide in Aqueous Media is Reversible: A Step by Step Conformational Analysis Suggests the Location of β Conformation Seeding

Linking folding with aggregation in Alzheimer's β-amyloid peptides

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

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