title: Ion channel formation by Alzheimer's disease amyloid beta-peptide (Abeta40) in unilamellar liposomes is determined by anionic phospholipids.
abstract: Incorporation of Alzheimer's disease amyloid beta-proteins (AbetaPs) across natural and artificial bilayer membranes leads to the formation of cation-selective channels. To study the peptide-membrane interactions involved in channel formation, we used cation reporter dyes to measure AbetaP-induced influx of Na+, Ca2+, and K+ into liposomes formed from phosphatidylserine (PS), phosphatidylinositol (PI) and phosphatidylcholine (PC). We found that Abeta40, but not Abeta40-1 or Abeta28, caused a dose-dependent increase in the concentration of each cation in the lumen of liposomes formed from the acidic phospholipids PS and PI. The Abeta40-induced changes in cation concentration, which we attribute to ion entry through Abeta40 channels, were not observed when using liposomes formed from the neutral phospholipid PC. Using mixtures of phospholipids, the magnitude of the AbetaP40-induced ion entry increased with the acidic phospholipid content of the liposomes, with entry being observed with as little as 5% PS or PI. Thus, while negatively charged phospholipids are required for formation of cation-permeable channels by Abeta40, a small amount is sufficient to support the process. These results have implications for the mechanisms of AbetaP cytotoxicity, suggesting that even a small amount of externalized negative charge could render cells susceptible to the deleterious effects of unregulated ion influx through AbetaP channels.
authors.affiliation: Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors.forename: Juan Marcos
authors.initials: JM
authors.lastname: Alarcón
authors.forename: Julio A
authors.initials: JA
authors.lastname: Brito
authors.forename: Tamara
authors.initials: T
authors.lastname: Hermosilla
authors.forename: Illani
authors.initials: I
authors.lastname: Atwater
authors.forename: David
authors.initials: D
authors.lastname: Mears
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rojas
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000502:physiology / Q000633:toxicity; D000838:Anions / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000378:metabolism*; D008081:Liposomes / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism* / Q000502:physiology / Q000633:toxicity; D010713:Phosphatidylcholines / Q000502:physiology; D010716:Phosphatidylinositols / Q000502:physiology; D010718:Phosphatidylserines / Q000502:physiology; D010743:Phospholipids / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D013050:Spectrometry, Fluorescence
chemical_list: D016229:Amyloid beta-Peptides; D000838:Anions; D007473:Ion Channels; D008081:Liposomes; D010446:Peptide Fragments; D010713:Phosphatidylcholines; D010716:Phosphatidylinositols; D010718:Phosphatidylserines; D010743:Phospholipids; C078592:amyloid beta-protein (1-40); D012964:Sodium; D002118:Calcium