Ion channel formation by Alzheimer's disease amyloid β-peptide (Aβ40) in unilamellar liposomes is determined by anionic phospholipids

Incorporation of Alzheimer's disease amyloid β-proteins (AβPs) 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 AβP-induced influx of Na⁺, Ca²⁺, and K⁺ into liposomes formed from phosphatidylserine (PS), phosphatidylinositol (PI) and phosphatidylcholine (PC). We found that Aβ40, but not Aβ40-1 or Aβ28, 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 Aβ40-induced changes in cation concentration, which we attribute to ion entry through Aβ40 channels, were not observed when using liposomes formed from the neutral phospholipid PC. Using mixtures of phospholipids, the magnitude of the AβP40-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 Aβ40, a small amount is sufficient to support the process. These results have implications for the mechanisms of AβP cytotoxicity, suggesting that even a small amount of externalized negative charge could render cells susceptible to the deleterious effects of unregulated ion influx through AβP channels.