CATIONIC LIPIDS (LIPOFECTAMINE) AND DISTURBANCE OF CELLULAR CHOLESTEROL AND SPHINGOMYELIN DISTRIBUTION MODULATES GAMMA-SECRETASE ACTIVITY WITHIN AMYLOID PRECURSOR PROTEIN IN-VITRO

To study beta-amyloid protein generation we expressed different amyloi d precursor protein (APP) isoforms in the human neuroblastoma cell lin e SY5Y (for details see (1)). Treatment with lipofectamine, an cationi c lipid for eucaryotic cell transfection, inhibits gamma-secretase act ivity 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 sh ow that disturbance of cellular cholesterol and sphingomyelin distribu tion in transfected SY5Y cells results in an overproduction of beta-am yloid protein. This provides experimental evidence that membrane insta bility influenced the proteolytic activity of gamma-secretase within t he APP molecule.