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

Habchi, Johnny; Chia, Sean; Galvagnion, Céline; Michaels, Thomas C.T.; Bellaiche, Mathias M.J.; Ruggeri, Francesco Simone; Sanguanini, Michele; Idini, Ilaria LU ; Kumita, Janet R. and Sparr, Emma LU , et al. (2018) In Nature Chemistry p.1-11
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... (More)

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.

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Contribution to journal
publication status
epub
subject
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Nature Chemistry
pages
11 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85046548678
ISSN
1755-4330
DOI
10.1038/s41557-018-0031-x
language
English
LU publication?
yes
id
d8cc9f84-9235-4bab-9823-80c04ff10d22
date added to LUP
2018-05-24 13:16:07
date last changed
2018-10-07 05:06:52
@article{d8cc9f84-9235-4bab-9823-80c04ff10d22,
  abstract     = {<p>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.</p>},
  author       = {Habchi, Johnny and Chia, Sean and Galvagnion, Céline and Michaels, Thomas C.T. and Bellaiche, Mathias M.J. and Ruggeri, Francesco Simone and Sanguanini, Michele and Idini, Ilaria and Kumita, Janet R. and Sparr, Emma and Linse, Sara and Dobson, Christopher M. and Knowles, Tuomas P.J. and Vendruscolo, Michele},
  issn         = {1755-4330},
  language     = {eng},
  month        = {05},
  pages        = {1--11},
  publisher    = {Nature Publishing Group},
  series       = {Nature Chemistry},
  title        = {Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes},
  url          = {http://dx.doi.org/10.1038/s41557-018-0031-x},
  year         = {2018},
}