MEMBRANE DISRUPTION BY ALZHEIMER BETA-AMYLOID PEPTIDES MEDIATED THROUGH SPECIFIC FINDING TO EITHER PHOSPHOLIPIDS OR GANGLIOSIDES - IMPLICATIONS FOR NEUROTOXICITY

Increasing evidence implicates A beta peptides as neurotoxic agents in Alzheimer's disease. We investigated one possible mechanism of neurot oxicity, namely A beta-membrane lipid interactions, We find that A bet a disruption membranes containing acidic phospholipids. This disruptio n is greater at slightly acidic pH (characteristic of endosomes) than at neutral pH (characteristic of the extracellular space). This pH dep endence suggests that A beta has the capacity to disrupt endosomal and plasma membranes, and this disruption could account, at least in part , for the observed neurotoxic effects of the peptide. We also find tha t gangliosides induce A beta to adopt a novel alpha/beta conformation at neutral pH.