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# Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer’s disease. Nat Chem

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Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106-9510, USA.
(Impact Factor: 25.33). 07/2009; 1(4):326-31. DOI: 10.1038/nchem.247
Source: PubMed

ABSTRACT In recent years, small protein oligomers have been implicated in the aetiology of a number of important amyloid diseases, such as type 2 diabetes, Parkinson's disease and Alzheimer's disease. As a consequence, research efforts are being directed away from traditional targets, such as amyloid plaques, and towards characterization of early oligomer states. Here we present a new analysis method, ion mobility coupled with mass spectrometry, for this challenging problem, which allows determination of in vitro oligomer distributions and the qualitative structure of each of the aggregates. We applied these methods to a number of the amyloid-β protein isoforms of Aβ40 and Aβ42 and showed that their oligomer-size distributions are very different. Our results are consistent with previous observations that Aβ40 and Aβ42 self-assemble via different pathways and provide a candidate in the Aβ42 dodecamer for the primary toxic species in Alzheimer's disease.

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Available from: Joan Shea, Sep 26, 2015
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• "[5] [6] [7] [8] [9] IMS has provided, for instance, a direct measure for the conformer preferences of solvent-free polypeptides, [10] [11] [12] [13] DNA complexes [14] and large protein complexes [15] [16] as well as oligomerization of protein fragments. [17] [18] Applications of IMS also include the separation of conformers of flexible molecules, such as biopolymers, and the determination of their possible solvent-free rearrangements while reacting with the site of the protein-coupled receptor. [19] Interpretation of IMS data critically relies on conformation search strategies; hence, various simulation methods have been applied to generate low-energy structures and to correlate them with experimentally determined collision cross section (CCS). "
##### Article: Separation of glycosidic catiomers by TWIM-MS using CO2 as a drift gas
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ABSTRACT: Traveling wave ion mobility mass spectrometry (TWIM-MS) is shown to be able to separate and characterize several isomeric forms of diterpene glycosides stevioside (Stv) and rebaudioside A (RebA) that are cationized by Na(+) and K(+) at different sites. Determination and characterization of these coexisting isomeric species, herein termed catiomers, arising from cationization at different and highly competitive coordinating sites, is particularly challenging for glycosides. To achieve this goal, the advantage of using CO2 as a more massive and polarizable drift gas, over N2 , was demonstrated. Post-TWIM-MS/MS experiments were used to confirm the separation. Optimization of the possible geometries and cross-sectional calculations for mobility peak assignments were also performed. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
Journal of Mass Spectrometry 02/2015; 50(2). DOI:10.1002/jms.3532 · 2.38 Impact Factor
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• "For instance, mutations that increase hydrophobicity of the Alzheimer's beta peptide Aβ1-42 have a pronounced effect on its aggregation behaviour and the size distribution of the resulting oligomers [23–26, 40], promoting toxicity and expediting the fibrillization process. In the same spirit, two extra hydrophobic residues in Aβ1-42 are believed to contribute to the more pronounced oligomerisation and faster fibrillization compared to its alloform Aβ1- 40 [24] [25] [40]. Temperature, pH, and concentration of certain metals also affect oligomerization and pathways of fibrillization [41] [42] [43] [44]. "
##### Article: Crucial role of non-specific interactions in amyloid nucleation
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ABSTRACT: Protein oligomers have been implicated as toxic agents in a wide range of amyloid-related diseases. Yet it has remained unsolved whether the oligomers are a necessary step in the formation of amyloid fibrils, or just a dangerous by-product. Analogously, it has not been resolved if the amyloid nucleation process is a classical one-step nucleation process, or a two-step process involving pre-nucleation clusters. We use coarse-grained computer simulations to study the effect of non-specific attractions between peptides on the primary nucleation process underlying amyloid fibrillization. We find that for peptides that do not attract, the classical one-step nucleation mechanism is possible, but only at non-physiologically high peptide concentrations. At low peptide concentrations, which mimic the physiologically relevant regime, attractive inter-peptide interactions are essential for fibril formation. Nucleation then inevitably takes place through a two-step mechanism involving prefibrillar oligomers. We show that oligomers not only help peptides meet each other, but create an environment that facilitates the conversion of monomers into the $\beta$-sheet rich form characteristic of fibrils. Nucleation typically does not proceed via the most prevalent oligomers, but via an oligomer size that is only observed in rare fluctuations, which is why such aggregates might be hard to capture experimentally. Finally, we find that the nucleation of amyloid fibrils cannot be described by classical nucleation theory: in the two-step mechanism the critical nucleus size increases both with an increase in concentration and in the inter-peptide interactions, in direct contrast with predictions from classical nucleation theory.
Proceedings of the National Academy of Sciences 12/2014; 111(50). DOI:10.1073/pnas.1410159111 · 9.67 Impact Factor
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• "The importance of residues 2–11 on membrane interaction has been underlined in another study, where the quantitative binding of aSN to isolated mitochondria was abolished when residues 2–11 were deleted [21]. Although neurodegenerative diseases such as PD and Alzheimer's Disease were initially mainly associated with amyloid deposits, there is growing consensus that non-or pre-fibrillar oligomeric species are the cytotoxic species [22] [23] [24] [25] [26] [27] [28]. This may be linked to their structure and ability to interact with membranes. "
##### Article: The N-terminus of α-synuclein is essential for both monomeric and oligomeric interactions with membranes
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ABSTRACT: The intrinsically disordered protein α-synuclein (αSN) is linked to Parkinson's Disease and forms both oligomeric species and amyloid fibrils. The N-terminal part of monomeric α SN interacts strongly with membranes and αSN cytotoxicity has been attributed to oligomers' ability to interact with and perturb membranes. We show that membrane folding of monomeric wt αSN and N-terminally truncated variants correlates with membrane permeabilization. Further, the first 11 N-terminal residues are crucial for monomers' and oligomers' interactions with and permeabilization of membranes. We attribute oligomer permeabilization both to cooperative electrostatic interactions through the N-terminus and interactions mediated by hydrophobic regions in the oligomer.
FEBS letters 12/2013; 588(3). DOI:10.1016/j.febslet.2013.12.015 · 3.17 Impact Factor