b-Amyloid peptides (Abs) bind to several G-protein coupled receptor proteins and stimulate GTPase activity in neurons. In this study we determined the effects of Ab(1-42), Ab(1-40), and their mixtures on [ 35 S]GTP binding in rat brain cortical membranes in the absence and presence of zinc. We found that the Abs alone induced a concentration-dependent activation of G-proteins (IC 50 10 )6 M), while aggregated Ab fibrils only affected GTP binding at concentrations above 10 )5 M. Mixing Ab(25-35) with Ab(1-42) or Ab(1-40) induced a several-fold increase in GTP-binding. This potentiation followed a bell shaped curve with a maximum at 50 : 50 ratios. No potentiating effect could be seen by mixing Ab(1-40) and Ab(1-42) or highly aggregated Abs. Zinc had no effect on Ab(1-40/42) but strongly potentiated the Ab(25-35) or the mixed peptides-induced GTP-binding. Changes in secondary structure accompanied the mixed peptides or the peptide/zinc complexes induced potentiation, revealing that structural alterations are behind the increased biological action. These concentration dependent potentiating effects of zinc and the peptide mixtures could be physiologically important at brain regions where peptide fragments and/or zinc are present at elevated concentrations.
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