Amyloid precursor protein carboxy-terminal fragments modulate G-proteins and adenylate cyclase activity in Alzheimer’s disease brain

• Published in: Brain research. Molecular brain research. Vol. 117; no. 1; pp. 73 - 82
• Main Authors: Mahlapuu, Riina, Viht, Kaido, Balaspiri, Lajos, Bogdanovic, Nenad, Saar, Külliki, Soomets, Ursel, Land, Tiit, Zilmer, Mihkel, Karelson, Ello, Langel, Ülo
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 10.09.2003; Elsevier
• Subjects: Acetylcysteine - administration & dosage; Adenylyl Cyclases - metabolism; Aged; Aged, 80 and over; Alzheimer Disease - enzymology; Alzheimer Disease - metabolism; Alzheimer’s disease; Amyloid beta-Protein Precursor - metabolism; APP C-terminus; Binding Sites; Biological and medical sciences; Case-Control Studies; Cell Membrane - drug effects; Cell Membrane - enzymology; Deferoxamine - administration & dosage; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dose-Response Relationship, Drug; Female; Free Radical Scavengers - pharmacology; Frontal Lobe - drug effects; Frontal Lobe - enzymology; G-protein; Glutathione - administration & dosage; GTP Phosphohydrolases - analysis; GTP-Binding Proteins - metabolism; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Hippocampus; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - enzymology; Humans; Hydrogen Peroxide - administration & dosage; Iron Chelating Agents; Medical sciences; Medicin och hälsovetenskap; Neurology; Oxidants; Oxidative stress; Peptide Fragments - chemistry; Peptide Fragments - classification; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Sulfur Isotopes; Disorders of the nervous systems; Oxidative stress; G-protein; APP C-terminus; Alzheimer’s disease; Hippocampus; Human; Nervous system diseases; Enzyme; Alzheimer disease; Central nervous system; Phosphorus-oxygen lyases; Lyases; Amyloid precursor protein; Cerebral disorder; C terminal-Sequence; Adenylate cyclase; Enzymatic activity; Peptide fragment; Central nervous system disease; Degenerative disease; Alzheimer's disease; Brain (vertebrata); G protein
• ISSN: 0169-328X; 1872-6941
• DOI: 10.1016/S0169-328X(03)00292-4

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 μM APP(639–648)–APP(657–676) (PEP1) causes a fivefold stimulation in the [ 35S]GTPγS-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]GTPγS-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]GTPγS-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.