Inhibition of the electrostatic interaction between beta-amyloid peptide and membranes prevents beta-amyloid-induced toxicity

The accumulation of beta-amyloid peptides (A beta) into senile plaques is one of the hallmarks of Alzheimer disease. Aggregated A beta is toxic to cells in culture and this has been considered to be the cause of neurodegeneration that occurs in the Alzheimer disease brain. The discovery of compounds that prevent A beta toxicity may lead to a better understanding of the processes involved and ultimately to possible therapeutic drugs, Low nanomolar concentrations of A beta 1-42 and the toxic fragment A beta 25-35 have been demonstrated to render cells more sensitive to subsequent insults as manifested by an increased sensitivity. to formazan crystals following MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) reduction, Formation of the toxic beta-sheet conformation by A beta peptides is increased by negatively charged membranes, Here we demonstrate that phloretin and exifone, dipolar compounds that decrease the effective negative charge of membranes, prevent association of A beta 1-40 and A beta 25-35 to negatively charged lipid vesicles and A beta induced cell toxicity, These results suggest that A beta toxicity is mediated through a nonspecific physicochemical interaction with cell membranes.