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Nat Chem. 2018 Jun;10(6):673-683. doi: 10.1038/s41557-018-0031-x. Epub 2018 May 7.

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

Author information

1
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK.
2
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
3
Paulson School for Engineering and Applied Sciences, Harvard University, Cambridge, USA.
4
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
5
Department of Biochemistry & Structural Biology, Center for Molecular Protein Science, Lund University, Lund, Sweden.
6
Division of Physical Chemistry, Department of Chemistry, Lund University, Lund, Sweden.
7
Department of Physics, Cavendish Laboratory, Cambridge, UK.
8
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK. mv245@cam.ac.uk.

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.

PMID:
29736006
DOI:
10.1038/s41557-018-0031-x
[Indexed for MEDLINE]

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