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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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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; Kumita, Janet R.; Sparr, Emma; Linse, Sara; Dobson, Christopher M.; Knowles, Tuomas P.J.; Vendruscolo, Michele.

I: Nature Chemistry, Vol. 10, Nr. 6, 06.2018, s. 673-683.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

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, nr. 6, s. 673-683. https://doi.org/10.1038/s41557-018-0031-x

APA

Habchi, J., Chia, S., Galvagnion, C., Michaels, T. C. T., Bellaiche, M. M. J., Ruggeri, F. S., ... 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

CBE

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. 10(6):673-683. https://doi.org/10.1038/s41557-018-0031-x

MLA

Vancouver

Author

Habchi, Johnny ; Chia, Sean ; Galvagnion, Céline ; Michaels, Thomas C.T. ; Bellaiche, Mathias M.J. ; Ruggeri, Francesco Simone ; Sanguanini, Michele ; Idini, Ilaria ; Kumita, Janet R. ; Sparr, Emma ; Linse, Sara ; Dobson, Christopher M. ; Knowles, Tuomas P.J. ; Vendruscolo, Michele. / Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes. I: Nature Chemistry. 2018 ; Vol. 10, Nr. 6. s. 673-683.

RIS

TY - JOUR

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

Y1 - 2018/6

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.

UR - http://www.scopus.com/inward/record.url?scp=85046548678&partnerID=8YFLogxK

U2 - 10.1038/s41557-018-0031-x

DO - 10.1038/s41557-018-0031-x

M3 - Article

VL - 10

SP - 673

EP - 683

JO - Nature Chemistry

T2 - Nature Chemistry

JF - Nature Chemistry

SN - 1755-4330

IS - 6

ER -