Cholesterol, a modulator of membrane-associated A beta-fibrillogenesis andneurotoxicity

Recent studies have suggested that cholesterol, an important determinant of the physical state of biological membranes, plays a significant role in th e development of Alzheimer's disease. We have employed in situ scanning pro be microscopy, fluorescence anisotropy, and electron microscopy to investig ate how cholesterol levels within total brain lipid bilayers effect amyloid beta -peptide (A beta)-assembly. Fluorescence anisotropy measurements reve aled that the relative fluidity of the total brain lipid membranes was infl uenced by the level of cholesterol and the addition of A beta 40 resulted i n a decrease in the overall vesicle fluidity. In situ scanning probe micros copy performed on supported planar bilayers of total brain lipid revealed a correlation between membrane fluidity, as influenced by fibrillogenesis. T hese observations were consistent with fluorescence microscopy studies of P C-12 and SH-SY5Y cell lines exposed to exogenous A beta, which revealed an inverse correlation between membrane cholesterol level, and A beta -cell su rface binding and subsequent cell death. These results collectively suggest that A beta -cell surface interactions are mediated by cellular cholestero l levels, the distribution of cholesterol throughout the cell, and membrane fluidity. (C) 2001 Academic Press.