title: Regulation of GTPase and adenylate cyclase activity by amyloid beta-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 beta-peptide, A beta (1-42), and its shorter fragments, A beta (12-28), A beta (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 A beta (25-35), whereas A beta (12-28) did not have any significant effect on the GTPase activity and only weakly influenced adenylate cyclase. A beta (1-42), similar to A beta (25-35), stimulated the GTPase activity in both tissues and adenylate cyclase activity in ventral hippocampal membranes. Surprisingly, A beta (1-42) did not have a significant effect on adenylate cyclase activity in the cortical membranes. At high concentrations of A beta (25-35) 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 Gi/G(o) proteins. Addition of glutathione and N-acetyl-L-cysteine, two well-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 (16-20), a hexapeptide shown previously to bind to the same sequence in A beta-peptide, and prevent fibril formation, decreased stimulation of adenylate cyclase activity by A beta (25-35), however, NMR diffusion measurements with the 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 strongly suggest that A beta and its fragments may affect G-protein coupled signal transduction systems, although the mechanism of this interaction is not fully understood.
authors.affiliation: Department of Neurochemistry and Neurotoxicology, Arrhenius Laboratories, Stockholm University, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Soomets
authors.forename: R
authors.initials: R
authors.lastname: Mahlapuu
authors.forename: R
authors.initials: R
authors.lastname: Tehranian
authors.forename: J
authors.initials: J
authors.lastname: Jarvet
authors.forename: E
authors.initials: E
authors.lastname: Karelson
authors.forename: M
authors.initials: M
authors.lastname: Zilmer
authors.forename: K
authors.initials: K
authors.lastname: Iverfeldt
authors.forename: M
authors.initials: M
authors.lastname: Zorko
authors.forename: A
authors.initials: A
authors.lastname: Gräslund
authors.forename: U
authors.initials: U
authors.lastname: Langel
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D004058:Diffusion; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D005978:Glutathione / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008566:Membranes / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology; D037342:Pertussis Toxin; D051381:Rats; D017208:Rats, Wistar; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D037361:Adenylate Cyclase Toxin; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D010446:Peptide Fragments; D010566:Virulence Factors, Bordetella; D000246:Adenosine Diphosphate Ribose; D037342:Pertussis Toxin; D020558:GTP Phosphohydrolases; D000262:Adenylyl Cyclases; D005978:Glutathione; D000111:Acetylcysteine