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

Modulation of GTPase and adenylate cyclase (ATP pyrophosphate-lyase, EC 4.6 .1.1) activity by Alzheimer's disease related amyloid beta-peptide, A beta( 1-42), and its shorter fragments, A beta(12-28), A beta(25-35), were studie d in isolated membranes from rat ventral hippocampus and frontal cortex. In both tissues, the activity of GTPase and adenylate cyclase was upregulated by A beta(25-35), whereas A beta(12-28) did not have any significant effec t on the GTPase activity and only weakly influenced adenylate cyclase. A be ta(1-42), similar to A beta(25-35), stimulated the GTPase activity in both tissues and adenylate cyclase activity in ventral hippocampal membranes. Su rprisingly, A beta(1-42) did not have a significant effect on adenylate cyc lase activity in the cortical membranes. At high concentrations of A beta(2 5-35) and A beta(1-42), decreased or no activation of adenylate cyclase was observed. The activation of GTPase at high concentrations of A beta(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 we ll-known antioxidants, at 1.5 and 0.5 mM, respectively, decreased A beta(25 -35) stimulated adenylate cyclase activity in both tissues. Lys-A beta(16-2 0), a hexapeptide shown previously to bind to the same sequence in A beta-p eptide, and prevent fibril formation, decreased stimulation of adenylate cy clase activity by A beta(25-35), however, NMR diffusion measurements with t he two peptides showed that this effect was not due to interactions between the two and that A beta(25-35) was active in a monomeric form. Our data st rongly suggest that A beta and its fragments may affect G-protein coupled s ignal transduction systems, although the mechanism of this interaction is n ot fully understood. (C) 1999 Elsevier Science B.V. All rights reserved.