G Protein and cAMP-Dependent Protein Kinase Mediate Amyloid β-Peptide Inhibition of Neuronal Glucose Uptake

• Published in: Experimental neurology 2001-01, Vol.167 (1), p.59-64
• Main Authors: Prapong, Teerasak, Uemura, Etsuro, Hsu, Walter H.
• Format: Article
• Language: English
• Subjects: Adenylyl Cyclases - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - pharmacology; Animals; Bucladesine - pharmacology; cAMP; Carbazoles; Cells, Cultured; Cholera Toxin - pharmacology; Colforsin - pharmacology; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - metabolism; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; G protein; Glucose - pharmacokinetics; glucose uptake; GTP-Binding Proteins - antagonists & inhibitors; GTP-Binding Proteins - metabolism; hippocampal neuron; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - metabolism; Indoles - pharmacology; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Pyrroles - pharmacology; Rats; Rats, Sprague-Dawley; β-amyloid
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1006/exnr.2000.7519

The mechanism by which amyloid β-peptide (Aβ) inhibits glucose uptake in cultured cells is not known. Here we demonstrated a signaling pathway in which Aβ25-35, a neurotoxic portion of the Aβ peptide corresponding to amino acids 25–35, inhibits neuronal glucose uptake by hippocampal neurons. The GP antagonist-2, which blocks Gs, prevented the inhibitory effect of Aβ on the glucose uptake. Exposure of cells to Aβ resulted in a transitory increase in intracellular levels of cAMP. To assess the role of cAMP in neuronal glucose uptake, cultured neurons were exposed to dibutyryl cAMP (Bt2cAMP) or an adenylyl cyclase activator, forskolin. Both Bt2cAMP and forskolin inhibited neuronal glucose uptake, and cAMP-dependent protein kinase (PKA) inhibitor KT5720 blocked the Aβ-mediated inhibition of glucose uptake. Cholera toxin, which stimulates adenylyl cyclase by activating Gs protein, also inhibited neuronal glucose uptake, and Aβ potentiated this inhibitory effect of cholera toxin on glucose uptake. Thus, our findings suggest that Aβ inhibits glucose uptake by activating the Gs-coupled receptors and involves the cAMP–PKA system.