Abstract
Aggregation of amyloid-β (Aβ) peptides is a characteristic pathological feature of Alzheimer's disease. We have exploited the relationship between solvent exposure and intrinsic fluorescence of a single tyrosine residue, Tyr10, in the Aβ sequence to probe structural features of the monomeric, oligomeric and fibrillar forms of the 42-residue Aβ1-42. By monitoring the quenching of Tyr10 fluorescence upon addition of water-soluble acrylamide, we show that in Aβ1-42 oligomers this residue is solvent-exposed to a similar extent to that found in the unfolded monomer. By contrast, Tyr10 is significantly shielded from acrylamide quenching in Aβ1-42 fibrils, consistent with its proximity to the fibrillar cross-β core. Furthermore, circular dichroism measurements reveal that Aβ1-42 oligomers have a considerably lower β-sheet content than the Aβ1-42 fibrils, indicative of a less ordered molecular arrangement in the former. Taken together these findings suggest significant differences in the structural assembly of oligomers and fibrils that are consistent with differences in their biological effects.
Highlights
Alzheimer's disease (AD) and a range of related disorders are associated with the self-assembly, aggregation, and fibril formation of disease-specific peptides and proteins [1]; in the case of AD such processes are involved with aggregation of the amyloid-b (Ab) peptide [2,3]
In its fibrillar form, this peptide is the main proteinaceous component of the extracellular plaque deposits that are characteristic of AD pathology [4,5], but in the brain Ab exists in a variety of monomeric and oligomeric forms [6]
It has been reported that soluble Ab concentrations correlate more closely with dementia than the amount of amyloid plaques [7,8], and soluble Ab oligomers are thought to be the main culprits in the pathogenesis of AD and related conditions [9], since they have been associated with impaired cognitive function [10e12] and have been shown to induce cellular toxicity [13e17]
Summary
Alzheimer's disease (AD) and a range of related disorders are associated with the self-assembly, aggregation, and fibril formation of disease-specific peptides and proteins [1]; in the case of AD such processes are involved with aggregation of the amyloid-b (Ab) peptide [2,3]. Aran Terol et al / Biochemical and Biophysical Research Communications 468 (2015) 696e701 microscopic architecture resembles that found in mature fibrils To address this issue, we have taken advantage of the fact that the Ab peptide contains only a single intrinsically fluorescent residue, tyrosine at position 10 (Tyr10), which is located in between the bcore and the flexible N-terminus of fibrillar Ab1-40 and Ab1-42. Our results indicate that Ab1-42 oligomers show the presence of a degree of b-sheet structure, but that they are distinctly less ordered than fibrils, and this is confirmed by a substantially higher degree of solvent exposure around Tyr10 Taken together these results highlight significant differences in the molecular architecture of the oligomeric versus the fibrillar forms of the Ab peptides which may offer new insights into the differential biological activities
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