Neuroprotective actions of Glucagon-like peptide-1 in differentiated human neuroprogenitor cells

Authors

  • Kalpana Velmurugan,

    1. Section of Endocrinology, Veterans Affairs Medical Center, Denver, Colorado, USA
    2. Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA
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  • Ron Bouchard,

    1. Section of Endocrinology, Veterans Affairs Medical Center, Denver, Colorado, USA
    2. Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA
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  • Gregory Mahaffey,

    1. Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA
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  • Subbiah Pugazhenthi

    Corresponding author
    1. Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA
    • Section of Endocrinology, Veterans Affairs Medical Center, Denver, Colorado, USA
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Address correspondence and reprints requests to Subbiah Pugazhenthi, Ph.D, Denver VA Medical Center and Department of Medicine University of Colorado Denver Mail Stop 8106, 12801 E 17th Ave Aurora, CO 80045, USA. E-mail: subbiah.pugazhenthi@ucdenver.edu

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.

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