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

Habchi, Johnny (author)
University of Cambridge
Chia, Sean (author)
University of Cambridge
Galvagnion, Céline (author)
University of Cambridge
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Michaels, Thomas C.T. (author)
University of Cambridge,Harvard University
Bellaiche, Mathias M.J. (author)
University of Cambridge,National Institute of Diabetes and Digestive and Kidney Diseases
Ruggeri, Francesco Simone (author)
University of Cambridge
Sanguanini, Michele (author)
University of Cambridge
Idini, Ilaria (author)
Lund University,Lunds universitet,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
Kumita, Janet R. (author)
University of Cambridge
Sparr, Emma (author)
Lund University,Lunds universitet,Fysikalisk kemi,Enheten för fysikalisk och teoretisk kemi,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Physical Chemistry,Physical and theoretical chemistry,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
Linse, Sara (author)
Lund University,Lunds universitet,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
Dobson, Christopher M. (author)
University of Cambridge
Knowles, Tuomas P.J. (author)
University of Cambridge
Vendruscolo, Michele (author)
University of Cambridge
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 (creator_code:org_t)
2018-05-07
2018
English.
In: Nature Chemistry. - : Springer Science and Business Media LLC. - 1755-4330 .- 1755-4349. ; 10:6, s. 673-683
Related links:
http://dx.doi.org/10...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

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