The effect of Alzheimer's Aβ aggregation state on the permeation of biomimetic lipid vesicles

Alzheimer's disease is characterized by the aggregation and deposition of the Aβ peptide. This 40 or 42 residue peptide is the product of the proteolysis of the amyloid precursor protein membrane protein and is able to assemble to form ordered, stable amyloid fibrils as well as small, soluble, and potentially cytotoxic oligomers. The toxicity of the oligomers may be associated with the ability to bind to and affect the integrity of lipid membranes. In this novel work, we have monitored and compared the ability of the potent Aβ42 peptide, the less amyloidogenic Aβ40 peptide, and a variant with reduced amyloidogenicity to bind to and affect the integrity of membranes using dye-filled synthetic vesicles. We reveal that the potency of the assemblies reduces with incubation time of the peptide and that maximal effect occurs when a particular species is apparent by electron microscopy. We have investigated the effect of lipid vesicle composition, and our results suggest that charge on the vesicles is important and that binding may partly be mediated by the GM1 ganglioside receptors expressed in the outer leaflet of vertebrate membranes.