Aβ42 oligomers, but not fibrils, simultaneously bind to and cause damage to ganglioside-containing lipid membranes

Abstract

Aβ (amyloid-β peptide) assembles to form amyloid fibres that accumulate in senile plaques associated with AD (Alzheimer's disease). The major constituent, a 42-residue Aβ, 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 may be associated with the ability of oligomers to associate with and cause permeation of lipid membranes. In the present study, we have investigated the ability of oligomeric and fibrillar Aβ42 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 approximately 2-fold less fluorophore leakage compared with oligomeric Aβ. Binding of the oligomers may be, in part, mediated by the GM1 ganglioside receptors as there is a 1.8-fold increase in oligomeric Aβ binding and a 2-fold increase in permeation compared with when GM1 is not present. Atomic force microscopy reveals the formation of defects and holes in response to oligomeric Aβ, but not preformed fibrillar Aβ. The results of the present study indicate that significant membrane disruption arises from association of low-molecular-mass Aβ and this may be mediated by mechanical damage to the membranes by Aβ aggregation. This membrane disruption may play a key role in the mechanism of Aβ-related cell toxicity in AD.

Anesthetic 2,2,2-trifluoroethanol induces amyloidogenesis and cytotoxicity in human serum albumin

“…This observed toxicity may be associated with the ability of oligomers to bind with and cause permeation of cell lipid membrane. The binding may partly be mediated by the GM1 (monosialo) ganglioside receptors expressed in the outer leaflet of vertebrate membrane [30]. Additionally, bar graph of tail lengths of HSA confirms the above results as deduced from images (Fig.…”

GM1 and GM2 gangliosides: recent developments

“…These results are in agreement with in vivo studies where aggregation seems to be increased at the level of membrane rafts (21,24,25). However, the binding of preformed Aβ oligomers and amylin aggregates to synthetic lipid vesicles, an event that induces membrane permeabilization, appears to be driven by GM1 (21,26). It has also been demonstrated that exogenous Aβ1-42 oligomers applied to cultured neurons tend to accumulate on the membrane at the level of rafts enriched in GM1 (25).…”

“…Extraction for the analysis of disease-associated changes (11) In vitro Biological membrane model (3,4,20,22,23,26,32) In vitro SIMS of individual isotope-labeled lipid components (3) In vitro Column of immobilized beads functionalized with a target protein and mass spectrometry (6) In vitro Single fluorescent molecule imaging and tracking (9,28,29) In vivo Molecular dynamics (5,35,36) In silico…”

Role of the Fast Kinetics of Pyroglutamate-Modified Amyloid-β Oligomers in Membrane Binding and Membrane Permeability

“…In comparison, oligomeric and fibrillar self-assembled structures of full-length Aβs were found to form on different supported membranes. 53−57 …”