Non-Amyloid-β Component of Human α-Synuclein Oligomers Induces Formation of New Aβ Oligomers: Insight into the Mechanisms That Link Parkinson's and Alzheimer's Diseases

Yoav Atsmon-Raz, Yifat Miller

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

(Figure Presented). Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs), of which their major component is the non-amyloid-β component (NAC) of α-synuclein (AS). Clinical studies have identified a link between PD and Alzheimer's disease (AD), but the question of why PD patients are at risk to develop various types of dementia, such as AD, is still elusive. In vivo studies have shown that Aβ can act as a seed for NAC/AS aggregation, promoting NAC/AS aggregation and thus contributing to the etiology of PD. However, the mechanisms by which NAC/AS oligomers interact with Aβ oligomers are still elusive. This work presents the interactions between NAC oligomers and Aβ oligomers at atomic resolution by applying extensive molecular dynamics simulations for an ensemble of cross-seeded NAC-Aβ1-42 oligomers. The main conclusions of this study are as follows: first, the cross-seeded NAC-Aβ1-42 oligomers represent polymorphic states, yet NAC oligomers prefer to interact with Aβ1-42 oligomers to form double-layer over single-layer conformations due to electrostatic/hydrophobic interactions; second, among the single-layer conformations, the NAC oligomers induce formation of new β-strands in Aβ1-42 oligomers, thus leading to new Aβ oligomer structures; and third, NAC oligomers stabilize the cross-β structure of Aβ oligomers, i.e., yielding compact Aβ fibril-like structures.

Original languageEnglish
Pages (from-to)46-55
Number of pages10
JournalACS Chemical Neuroscience
Volume7
Issue number1
DOIs
StatePublished - 20 Jan 2016

Keywords

  • Alzheimer's disease
  • NAC
  • Parkinson's disease
  • amyloid β, α-synuclein
  • amyloids
  • cross-seeding
  • peptides
  • self-assembly

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