Dataset Information

Different Aggregation Pathways and Structures for A?40 and A?42 Peptides.

ABSTRACT: Self-aggregation of amyloid-? (A?) peptides has been known to play a vital role in the onset stage of neurodegenerative diseases, indicating the necessity of understanding the aggregation process of A? peptides. Despite previous studies on the aggregation process of A? peptides, the aggregation pathways of A? isoforms (i.e., A?40 and A?42) and their related structures have not been fully understood yet. Here, we study the aggregation pathways of A?40 and A?42, and the structures of A?40 and A?42 aggregates during the process, based on fluorescence and atomic force microscopy (AFM) experiments. It is shown that in the beginning of aggregation process for both A?40 and A?42, a number of particles (i.e., spherical oligomers) are formed. These particles are subsequently self-assembled together, resulting in the formation of different shapes of amyloid fibrils. Our finding suggests that the different aggregation pathways of A? isoforms lead to the amyloid fibrils with contrasting structure.

SUBMITTER: Wang L

PROVIDER: S-EPMC7912290 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Different Aggregation Pathways and Structures for Aβ40 and Aβ42 Peptides.

Wang Li L Eom Kilho K Kwon Taeyun T

Biomolecules 20210130 2

Self-aggregation of amyloid-β (Aβ) peptides has been known to play a vital role in the onset stage of neurodegenerative diseases, indicating the necessity of understanding the aggregation process of Aβ peptides. Despite previous studies on the aggregation process of Aβ peptides, the aggregation pathways of Aβ isoforms (i.e., Aβ40 and Aβ42) and their related structures have not been fully understood yet. Here, we study the aggregation pathways of Aβ40 and Aβ42, and the structures of Aβ40 and Aβ42 ...[more]

PMID: 33573350

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Project description:Oligomers of amyloid β-protein (Aβ) are thought to be the proximal toxic agents initiating the neuropathologic process in Alzheimer's disease (AD). Therefore, targeting the self-assembly and oligomerization of Aβ has been an important strategy for designing AD therapeutics. In parallel, research into the metallobiology of AD has shown that Zn2+ can strongly modulate the aggregation of Aβ in vitro and both promote and inhibit the neurotoxicity of Aβ, depending on the experimental conditions. Thus, successful inhibitors of Aβ self-assembly may have to inhibit the toxicity not only of Aβ oligomers themselves but also of Aβ-Zn2+ complexes. However, there has been relatively little research investigating the effects of Aβ self-assembly and toxicity inhibitors in the presence of Zn2+. Our group has characterized previously a series of Aβ42 C-terminal fragments (CTFs), some of which have been shown to inhibit Aβ oligomerization and neurotoxicity. Here, we asked whether three CTFs shown to be potent inhibitors of Aβ42 toxicity maintained their activity in the presence of Zn2+. Biophysical analysis showed that the CTFs had different effects on oligomer, β-sheet, and fibril formation by Aβ42-Zn2+ complexes. However, cell viability experiments in differentiated PC-12 cells incubated with Aβ42-Zn2+ complexes in the absence or presence of these CTFs showed that the CTFs completely lost their inhibitory activity in the presence of Zn2+ even when applied at 10-fold excess relative to Aβ42. In light of these results, we tested another inhibitor, the molecular tweezer CLR01, which coincidentally had been shown to have a high affinity for Zn2+, suggesting that it could disrupt both Aβ42 oligomerization and Aβ42-Zn2+ complexation. Indeed, we found that CLR01 effectively inhibited the toxicity of Aβ42-Zn2+ complexes. Moreover, it did so at a lower concentration than needed for inhibiting the toxicity of Aβ42 alone. In agreement with these results, CLR01 inhibited β-sheet and fibril formation in Aβ42-Zn2+ complexes. Our data suggest that, for the development of efficient therapeutic agents, inhibitors of Aβ self-assembly and toxicity should be examined in the presence of relevant metal ions and that molecular tweezers may be particularly attractive candidates for therapy development.

Dataset Information

Different Aggregation Pathways and Structures for A?40 and A?42 Peptides.

Publications

Different Aggregation Pathways and Structures for Aβ40 and Aβ42 Peptides.

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