Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes

Research output: Contribution to journalArticle

Abstract

Alzheimer’s disease is a neurodegenerative disorder associated with the aberrant aggregation of the amyloid-β peptide. Although increasing evidence implicates cholesterol in the pathogenesis of Alzheimer’s disease, the detailed mechanistic link between this lipid molecule and the disease process remains to be fully established. To address this problem, we adopt a kinetics-based strategy that reveals a specific catalytic role of cholesterol in the aggregation of Aβ42 (the 42-residue form of the amyloid-β peptide). More specifically, we demonstrate that lipid membranes containing cholesterol promote Aβ42 aggregation by enhancing its primary nucleation rate by up to 20-fold through a heterogeneous nucleation pathway. We further show that this process occurs as a result of cooperativity in the interaction of multiple cholesterol molecules with Aβ42. These results identify a specific microscopic pathway by which cholesterol dramatically enhances the onset of Aβ42 aggregation, thereby helping rationalize the link between Alzheimer’s disease and the impairment of cholesterol homeostasis.

Details

Authors
  • Johnny Habchi
  • Sean Chia
  • Céline Galvagnion
  • Thomas C.T. Michaels
  • Mathias M.J. Bellaiche
  • Francesco Simone Ruggeri
  • Michele Sanguanini
  • Ilaria Idini
  • Janet R. Kumita
  • Emma Sparr
  • Sara Linse
  • Christopher M. Dobson
  • Tuomas P.J. Knowles
  • Michele Vendruscolo
Organisations
External organisations
  • University of Cambridge
  • Harvard University
  • National Institute of Diabetes and Digestive and Kidney Diseases
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biochemistry and Molecular Biology
Original languageEnglish
Pages (from-to)673-683
JournalNature Chemistry
Volume10
Issue number6
Early online date2018 May 7
Publication statusPublished - 2018 Jun
Publication categoryResearch
Peer-reviewedYes