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.
References
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Nat Med.
1996;
2
864-870
j.mclaurin@utoronto.ca
