title: Neuroprotective actions of glucagon-like peptide-1 in differentiated human neuroprogenitor cells.
abstract: Glucagon-like peptide-1 (GLP-1)-based therapies are currently available for the treatment of type 2 diabetes, based on their actions on pancreatic β cells. GLP-1 is also known to exert neuroprotective actions. To determine its mechanism of action, we developed a neuron-rich cell culture system by differentiating human neuroprogenitor cells in the presence of a combination of neurotrophins and retinoic acid. The neuronal nature of these cells was characterized by neurogenesis pathway-specific array. GLP-1 receptor expression was seen mainly in the neuronal population. Culture of neurons in the presence of Aβ oligomers resulted in the induction of apoptosis as shown by the activation of caspase-3 and caspase-6. Exendin-4, a long-acting analog of GLP-1, protected the neurons from apoptosis induced by Aβ oligomers. Exendin-4 stimulated cyclic AMP response element binding protein phosphorylation, a regulatory step in its activation. A transient transfection assay showed induction of a reporter linked to CRE site-containing human brain-derived neurotrophic factor promoter IV, by the growth factor through multiple signaling pathways. The anti-apoptotic action of exendin-4 was lost following down-regulation of cAMP response element binding protein. Withdrawal of neurotrophins resulted in the loss of neuronal phenotype of differentiated neuroprogenitor cells, which was prevented by incubation in the presence of exendin-4. Diabetes is a risk factor in the pathogenesis of Alzheimer's disease. Our findings suggest that GLP-1-based therapies can decrease the incidence of Alzheimer's disease among aging diabetic population.
authors.affiliation: Section of Endocrinology, Veterans Affairs Medical Center, Denver, Colorado 80045, USA.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Velmurugan
authors.forename: Ron
authors.initials: R
authors.lastname: Bouchard
authors.forename: Gregory
authors.initials: G
authors.lastname: Mahaffey
authors.forename: Subbiah
authors.initials: S
authors.lastname: Pugazhenthi
mesh_terms: D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D009434:Neural Pathways / Q000502:physiology; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D052216:Glucagon-Like Peptide 1