Ion channel formation by Alzheimer's disease amyloid beta-peptide (A beta 40) in unilamellar liposomes is determined by anionic phospholipids

Abstract

Incorporation of Alzheimer's disease amyloid beta-proteins (A beta Ps) 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 APP-induced influx of Na+, Ca2(+), and K+ into liposomes formed from phosphatidylserine (PS), phosphatidylinositol (PI) and phosphatidylcholine (PC). We found that A beta 40, but not A beta 40-1 orAP28, 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 A beta 40-induced changes in cation concentration, which we attribute to ion entry through A beta 40 channels, were not observed when using liposomes formed from the neutral phospholipid PC. Using mixtures of phospholipids, the magnitude of the A beta P40-induced ion entry increased with the acidic phospholipid content of the liposomes, with entry being observed with as little as S% PS or PI. Thus, while negatively charged phospholipids are required for formation of cation-permeable channels by A beta 40, a small amount is sufficient to support the process. These results have implications for the mechanisms of A beta P cytotoxicity, suggesting that even a small amount of externalized negative charge could render cells susceptible to the deleterious effects of unregulated ion influx through A beta P channels.