Amyloid precursor protein carboxy-terminal fragments modulate G-proteins and adenylate cyclase activity in Alzheimer's disease brain.
The influence of three C-terminal sequences and of transmembrane domain from amyloid precursor protein (APP) on the activity of G-proteins and of the coupled cAMP-signalling system in the postmortem Alzheimer's disease (AD) and age-matched control brains was compared. 10 microM APP(639-648)-APP(657-676) (PEP1) causes a fivefold stimulation in the [35S]GTPgammaS-binding to control hippocampal G-proteins. APP(657-676) (PEP2) and APP(639-648) (PEP4) showed less pronounced stimulation whereas cytosolic APP(649-669) (PEP3) showed no regulatory activity in the [35S]GTPgammaS-binding. PEP1 also showed 1.4-fold stimulatory effect of on the high-affinity GTPase and adenylate cyclase activity in control membranes, whereas in AD hippocampal membranes the stimulatory effect of PEP1 was substantially weaker. The PEP1 stimulation of the [35S]GTPgammaS-binding to the control membranes was significantly reduced by 1.5 mM glutathione, 0.5 mM antioxidant N-acetylcysteine and, in the greatest extent, by 0.01 mM of desferrioxamine. In AD hippocampus these antioxidants revealed no remarkable reducing effect on PEP1-induced stimulation. Our results suggest that C-terminal and transmembrane APP sequences possess receptor-like G-protein activating function in human hippocampus and that abnormalities of this function contribute to AD progression. The stimulatory action of these sequences on G-protein mediated signalling suggests the region-specific formation of reactive species.
D000111:Acetylcysteine / Q000008:administration & dosage; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001665:Binding Sites; D016022:Case-Control Studies; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D003676:Deferoxamine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000201:enzymology; D020558:GTP Phosphohydrolases / Q000032:analysis; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005978:Glutathione / Q000008:administration & dosage; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000008:administration & dosage; D007502:Iron Chelating Agents; D016877:Oxidants; D010446:Peptide Fragments / Q000737:chemistry / Q000145:classification / Q000378:metabolism / Q000494:pharmacology; D013460:Sulfur Isotopes
D016564:Amyloid beta-Protein Precursor; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D016877:Oxidants; D010446:Peptide Fragments; D013460:Sulfur Isotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006861:Hydrogen Peroxide; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D005978:Glutathione; D003676:Deferoxamine; D000111:Acetylcysteine