Enhanced G-protein activation by a mixture of Aβ(25-35), Aβ(1-40/42) and zinc

β-Amyloid peptides (Aβs) bind to several G-protein coupled receptor proteins and stimulate GTPase activity in neurons. In this study we determined the effects of Aβ(1-42), Aβ(1-40), Aβ(25-35) and their mixtures on [³⁵S]GTP binding in rat brain cortical membranes in the absence and presence of zinc. We found that the Aβs alone induced a concentration-dependent activation of G-proteins (IC₅₀ ∼ 10 ^-6 M), while aggregated Aβ fibrils only affected GTP binding at concentrations above 10-5 M. Mixing Aβ(25-35) with Aβ(1-42) or Aβ(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 Aβ(1-40) and Aβ(1-42) or highly aggregated Aβs. Zinc had no effect on Aβ(1-40/42) but strongly potentiated the Aβ(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.