title: Inhibition of the electrostatic interaction between beta-amyloid peptide and membranes prevents beta-amyloid-induced toxicity.
abstract: The accumulation of beta-amyloid peptides (Abeta) into senile plaques is one of the hallmarks of Alzheimer disease. Aggregated Abeta 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 Abeta toxicity may lead to a better understanding of the processes involved and ultimately to possible therapeutic drugs. Low nanomolar concentrations of Abeta1-42 and the toxic fragment Abeta25-35 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 Abeta 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 Abeta1-40 and Abeta25-35 to negatively charged lipid vesicles and Abeta induced cell toxicity. These results suggest that Abeta toxicity is mediated through a nonspecific physicochemical interaction with cell membranes.
authors.affiliation: Preclinical Research, Pharma Division, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Hertel
authors.forename: E
authors.initials: E
authors.lastname: Terzi
authors.forename: N
authors.initials: N
authors.lastname: Hauser
authors.forename: R
authors.initials: R
authors.lastname: Jakob-Rotne
authors.forename: J
authors.initials: J
authors.lastname: Seelig
authors.forename: J A
authors.initials: JA
authors.lastname: Kemp
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000502:physiology / Q000633:toxicity*; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D055672:Static Electricity
chemical_list: D016229:Amyloid beta-Peptides