Molecular insights into the primary nucleation of polymorphic amyloid β dimers in DOPC lipid bilayer membrane

Olga Press-Sandler, Yifat Miller

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Alzheimer's disease (AD) pathology is characterized by loss of memory cognitive and behavioral deterioration. One of the hallmarks of AD is amyloid β (Aβ) plaques in the brain that consists of Aβ oligomers and fibrils. It is accepted that oligomers, particularly dimers, are toxic species that are produced extracellularly and intracellularly in membranes. It is believed that the disruption of membranes by polymorphic Aβ oligomers is the key for the pathology of AD. This is a first study that investigate the effect of polymorphic “α-helix/random coil” and “fibril-like” Aβ dimers on 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membrane. It has been found that the DOPC membrane promotes Aβ1–42 “fibril-like” dimers and impedes Aβ1–42 “α-helix/random coil” dimers. The N-termini domains within Aβ1–42 dimers play a role in Aβ aggregation in membrane milieus. In addition, the aromatic π–π interactions (involving residues F19 and F20 in Aβ1–42) are the driving forces for the hydrophobic interactions that initiate the primary nucleation of polymorphic Aβ1–42 dimers within DOPC membrane. Finally, the DOPC bilayer membrane thickness is locally decreased, and it is disrupted by an embedded distinct Aβ1–42 dimer, due to relatively large contacts between Aβ1–42 monomers and the DOPC membrane. This study reveals insights into the molecular mechanisms by which polymorphic early-stage Aβ1–42 dimers have distinct impacts on DOPC membrane.

Original languageEnglish
Article numbere4283
JournalProtein Science
Volume31
Issue number5
Early online date7 Feb 2022
DOIs
StatePublished - 4 Apr 2022

Keywords

  • Alzheimer's disease
  • amyloids
  • DOPC membrane
  • neurodegenerative disease
  • protein aggregation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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