Cationic Lipids (Lipofectamine) and Disturbance of Cellular Cholesterol and Sphingomyelin Distribution Modulates Gamma-Secretase Activity Within Amyloid Precursor Protein In Vitro

Abstract To study beta-amyloid protein generation we expressed different amyloid precursor protein (APP) isoforms in the human neuroblastoma cell line SY5Y (for details see [1] ). Treatment with lipofectamine, an cationic lipid for eucaryotic cell transfection, inhibits gamma-secretase activity and stimulates the physiological APP cleavage by alpha-secretase activity. Beside the MDL inhibitor [2] , this is the second agent that shows modulation of gamma-secretase activity in vitro . Further, we show that disturbance of cellular cholesterol and sphingomyelin distribution in transfected SY5Y cells results in an overproduction of beta-amyloid protein. This provides experimental evidence that membrane instability influenced the proteolytic activity of gamma-secretase within the APP molecule.