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

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

doi:10.1038/s41557-018-0031-x

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

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

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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.

Original language	English
Journal	Nature Chemistry
Volume	10
Issue number	6
Pages (from-to)	673-683
Number of pages	11
ISSN	1755-4330
DOIs	https://doi.org/10.1038/s41557-018-0031-x
Publication status	Published - 1 Jun 2018
Externally published	Yes

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Habchi, J., Chia, S., Galvagnion, C., Michaels, T. C. T., Bellaiche, M. M. J., Ruggeri, F. S., Sanguanini, M., Idini, I., Kumita, J. R., Sparr, E., Linse, S., Dobson, C. M., Knowles, T. P. J., & Vendruscolo, M. (2018). Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes. Nature Chemistry, 10(6), 673-683. https://doi.org/10.1038/s41557-018-0031-x

Habchi, J, Chia, S, Galvagnion, C, Michaels, TCT, Bellaiche, MMJ, Ruggeri, FS, Sanguanini, M, Idini, I, Kumita, JR, Sparr, E, Linse, S, Dobson, CM, Knowles, TPJ & Vendruscolo, M 2018, 'Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes', Nature Chemistry, vol. 10, no. 6, pp. 673-683. https://doi.org/10.1038/s41557-018-0031-x

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title = "Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes",

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.",

author = "Johnny Habchi and Sean Chia and C{\'e}line Galvagnion and Michaels, {Thomas C T} and Bellaiche, {Mathias M J} and Ruggeri, {Francesco Simone} and Michele Sanguanini and Ilaria Idini and Kumita, {Janet R} and Emma Sparr and Sara Linse and Dobson, {Christopher M} and Knowles, {Tuomas P J} and Michele Vendruscolo",

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doi = "10.1038/s41557-018-0031-x",

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T1 - Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes

AU - Habchi, Johnny

AU - Chia, Sean

AU - Galvagnion, Céline

AU - Michaels, Thomas C T

AU - Bellaiche, Mathias M J

AU - Ruggeri, Francesco Simone

AU - Sanguanini, Michele

AU - Idini, Ilaria

AU - Kumita, Janet R

AU - Sparr, Emma

AU - Linse, Sara

AU - Dobson, Christopher M

AU - Knowles, Tuomas P J

AU - Vendruscolo, Michele

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41557-018-0031-x

DO - 10.1038/s41557-018-0031-x

M3 - Journal article

C2 - 29736006

SN - 1755-4330

VL - 10

SP - 673

EP - 683

JO - Nature Chemistry

JF - Nature Chemistry

IS - 6

ER -

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

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