Abstract
The coordination of zinc ions by histidine residues of amyloid-beta peptide (Aβ) plays a critical role in the zinc-induced Aβ aggregation implicated in Alzheimer’s disease (AD) pathogenesis. The histidine to arginine substitution at position 6 of the Aβ sequence (H6R, English mutation) leads to an early onset of AD. Herein, we studied the effects of zinc ions on the aggregation of the Aβ42 peptide and its isoform carrying the H6R mutation (H6R-Aβ42) by circular dichroism spectroscopy, dynamic light scattering, turbidimetric and sedimentation methods, and bis-ANS and thioflavin T fluorescence assays. Zinc ions triggered the occurrence of amorphous aggregates for both Aβ42 and H6R-Aβ42 peptides but with distinct optical properties. The structural difference of the formed Aβ42 and H6R-Aβ42 zinc-induced amorphous aggregates was also supported by the results of the bis-ANS assay. Moreover, while the Aβ42 peptide demonstrated an increase in the random coil and β-sheet content upon complexing with zinc ions, the H6R-Aβ42 peptide showed no appreciable structural changes under the same conditions. These observations were ascribed to the impact of H6R mutation on a mode of zinc/peptide binding. The presented findings further advance the understanding of the pathological role of the H6R mutation and the role of H6 residue in the zinc-induced Aβ aggregation.
Highlights
The aggregation of amyloid-β peptide (Aβ) is considered as a crucial event in pathogenesis of Alzheimer’s disease (AD)—a devastating neurodegenerative disorder which affects tens of millions of people throughout the world [1]
The Zn2+-Induced Aggregation of Aβ42 and H6R-Aβ42 Peptides Measured with Turbidity, dynamic light scattering (DLS), and Sedimentation Methods
In the absence of Zn2+, the species with a characteristic size of about 14–17 nm were detected by DLS in the Aβ42 and H6R-Aβ42 solutions within the 30-min incubation interval that may be attributed to the presence of low molecular weight Aβ42 oligomers [24]
Summary
The aggregation of amyloid-β peptide (Aβ) is considered as a crucial event in pathogenesis of Alzheimer’s disease (AD)—a devastating neurodegenerative disorder which affects tens of millions of people throughout the world [1]. Among factors which can potentially contribute to the in vivo Aβ aggregation, zinc ions (Zn2+) have attracted a constant interest [4,5] ever since they were found to trigger rapid Aβ aggregation in vitro [6]. The transgenic AD model mice with a knocked-out gene coding for the specific zinc transporter Zn-T3 (responsible for pumping zinc into synaptic vesicles) do not develop amyloid plaques [11]. The plausible role of zinc in AD pathogenesis as a causative agent alongside that of another vital metal such as copper has inspired a development of the approach known as “AD chelation therapy” [12], as a part of efforts to find a cure for the disease
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