Journal
NATURE CHEMISTRY
Volume 10, Issue 6, Pages 673-683Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41557-018-0031-x
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Funding
- Centre for Misfolding Diseases
- Agency for Science, Technology and Research, Singapore
- Marie Sklodowska-Curie Actions - Individual Fellowship
- Peterhouse College, Cambridge
- Swiss National Science Foundation
- NIH-Oxford/Cambridge Scholars Program
- Cambridge Commonwealth, European and International Trust
- Knut & Alice Wallenberg Foundation
- European Research Council
- Swedish Research Council
- Frances and Augustus Newman Foundation
- UK Biotechnology and Biochemical Sciences Research Council
- Wellcome Trust
- Intramural Research Program of the National Institute of Diabetes and Kidney Diseases, NIH
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Alzheimer's disease is a neurodegenerative disorder associated with the aberrant aggregation of the amyloid-beta 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 A beta 42 (the 42-residue form of the amyloid-beta peptide). More specifically, we demonstrate that lipid membranes containing cholesterol promote A beta 42 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 A beta 42. These results identify a specific microscopic pathway by which cholesterol dramatically enhances the onset of A beta 42 aggregation, thereby helping rationalize the link between Alzheimer's disease and the impairment of cholesterol homeostasis.
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