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Pharmacopsychiatry 2003; 36: 130-135
DOI: 10.1055/s-2003-43054
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Cholesterol, a Modulator of Membrane-associated Aβ-fibrillogenesis

J. McLaurin1 , A. A. Darabie1 , M. R. Morrison1
  • 1Centre for Research in Neurodegenerative Diseases and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
Further Information

Publication History

Publication Date:
22 October 2003 (online)

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One of the major pathological features of Alzheimer’s disease is the presence of extracellular amyloid plaques that are predominantly composed of the amyloid-β peptide (Aβ). Characterisation of plaques demonstrated the predominance of two peptides differing at the carboxyl terminus by 2 hydrophobic amino acids, Aβ40 and Aβ42. Diffuse plaques associated with AD are composed predominantly of Aβ42, whereas senile plaques contain both Aβ40 and Aβ42. Recently, it has been suggested that diffuse plaque formation is initiated as a plasma membrane bound Aβ species and that Aβ42 is the critical component. In order to investigate this hypothesis, we have examined Aβ40/42-lipid interactions using in situ atomic force microscopy, electron microscopy and fluorescence anisotropy. While the association of Aβ42 with planar bilayers resulted in peptide aggregation but no fibre formation, this was not the case for Aβ40 where we observed preferential fibre formation. Cholesterol, a key membrane component and modulating factor in AD, is inversely correlated with the extent of Aβ40/42-bilayer interaction. These results were confirmed using fluorescence anisotropy to evaluate the effect of Aβ on membrane fluidity and fluorimetry to confirm membrane integrity. Our results suggest that the enhanced amyloidogenic properties of Aβ42 are not correlated with fibril formation but aggregation on bilayer surfaces.

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Dr. JoAnne McLaurin

Centre for Research in Neurodegenerative Diseases

Tanz Neuroscience Building

Queen’s Park Crescent West

Toronto

Ontario

Canada

M5S 3H2

Phone: (416) 978-1035

Fax: (416) 978-1878

Email: j.mclaurin@utoronto.ca

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