Membrane disruption by Alzheimer beta-amyloid peptides mediated through specific binding to either phospholipids or gangliosides. Implications for neurotoxicity.
Increasing evidence implicates Abeta peptides as neurotoxic agents in Alzheimer's disease. We investigated one possible mechanism of neurotoxicity, namely Abeta-membrane lipid interactions. We find that Abeta disrupts membranes containing acidic phospholipids. This disruption is greater at slightly acidic pH (characteristic of endosomes) than at neutral pH (characteristic of the extracellular space). This pH dependence suggests that Abeta 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 that gangliosides induce Abeta to adopt a novel alpha/beta conformation at neutral pH.
McLaurin
J
J
Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
Chakrabartty
A
A
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002462:Cell Membrane; D002942:Circular Dichroism; D004396:Coloring Agents; D005732:Gangliosides / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D009498:Neurotoxins / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D011487:Protein Conformation
D016229:Amyloid beta-Peptides; D004396:Coloring Agents; D005732:Gangliosides; D009498:Neurotoxins; D010743:Phospholipids