Regulation of GTPase and adenylate cyclase activity by amyloid β-peptide and its fragments in rat brain tissue

Abstract

Modulation of GTPase and adenylate cyclase (ATP pyrophosphate-lyase, EC 4.6.1.1) activity by Alzheimer's disease related amyloid β-peptide, Aβ(1–42), and its shorter fragments, Aβ(12–28), Aβ(25–35), were studied in isolated membranes from rat ventral hippocampus and frontal cortex. In both tissues, the activity of GTPase and adenylate cyclase was upregulated by Aβ(25–35), whereas Aβ(12–28) did not have any significant effect on the GTPase activity and only weakly influenced adenylate cyclase. Aβ(1–42), similar to Aβ(25–35), stimulated the GTPase activity in both tissues and adenylate cyclase activity in ventral hippocampal membranes. Surprisingly, Aβ(1–42) did not have a significant effect on adenylate cyclase activity in the cortical membranes. At high concentrations of Aβ(25–35) and Aβ(1–42), decreased or no activation of adenylate cyclase was observed. The activation of GTPase at high concentrations of Aβ(25–35) was pertussis toxin sensitive, suggesting that this effect is mediated by G i/G o proteins. Addition of glutathione and N-acetyl- l-cysteine, two well-known antioxidants, at 1.5 and 0.5 mM, respectively, decreased Aβ(25–35) stimulated adenylate cyclase activity in both tissues. Lys-Aβ(16–20), a hexapeptide shown previously to bind to the same sequence in Aβ-peptide, and prevent fibril formation, decreased stimulation of adenylate cyclase activity by Aβ(25–35), however, NMR diffusion measurements with the two peptides showed that this effect was not due to interactions between the two and that Aβ(25–35) was active in a monomeric form. Our data strongly suggest that Aβ and its fragments may affect G-protein coupled signal transduction systems, although the mechanism of this interaction is not fully understood.