Alzheimer's Ab42 oligomers but not fibrils simultaneously bind to and cause damage to ganglioside containing lipid membranes

Thomas L Willliams , Benjamin R.G Johnson , Brigita Urbanc , Toby A Jenkins , Simon D.A Connell , Louise C Serpell (1)

1 School of Life Sciences.

Amyloid-Beta peptide (Ab) assembles to form amyloid fibres that accumulate in senile plaques associated with Alzheimer's disease (AD). The major constituent, a 42-residue Ab peptide, has the propensity to assemble and form soluble and potentially cytotoxic oligomers as well as ordered, stable amyloid fibres. It is widely believed that the cytotoxicity is a result of the formation of transient soluble oligomers. This observed toxicity maybe associated with the ability of oligomers to associate with and cause permeation of lipid membranes. Here, we have investigated the ability of oligomeric and fibrillar Ab42 to simultaneously associate with and affect the integrity of biomimetic membranes in vitro. Surface Plasmon field enhanced Fluorescence spectroscopy reveals that the binding of the freshly dissolved, oligomeric 42-residue peptide binds with a two-step association with the lipid bilayer and causes disruption of the membrane resulting in leakage from vesicles. In contrast, fibrils bind with a 2-fold reduced avidity and their addition results in around 2-fold less fluorophore leakage compared to oligomeric Ab. Binding of the oligomers may be in part mediated by the GM1 ganglioside receptors showing a 1.8-fold increase in oligomeric Ab binding and a 2-fold increase in permeation compared to when GM1 is not present. Atomic Force Microscopy reveals the formation of defects and holes in response to oligomeric Ab, but not preformed fibrillar Ab. Our results indicate significant membrane disruption arises from association of low molecular weight Ab and this may be mediated by mechanical damage to the membranes by Ab aggregation. This membrane disruption may play a key role in the mechanism Ab-related cell toxicity in Alzheimer's disease.

Mots clés: Life Sciences

Thomas L Willliams, Benjamin R.G Johnson, Brigita Urbanc, Toby A Jenkins, Simon D.A Connell, et al.. Alzheimer's Ab42 oligomers but not fibrils simultaneously bind to and cause damage to ganglioside containing lipid membranes. Biochemical Journal, 2011, 439 (1), pp.67-77. ⟨10.1042/BJ20110750⟩. ⟨hal-00628668⟩