Abstract
Glucagon-like peptide-1(7-36)-amide (GLP-1) is an endogenous insulinotropic peptide that is secreted from the gastrointestinal tract in response to food. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. GLP-1 receptors, which are coupled to the cyclic AMP second messenger pathway, are expressed throughout the brains of rodents and humans. It was recently reported that GLP-1 and exendin-4, a naturally occurring, more stable analogue of GLP-1 that binds at the GLP-1 receptor, possess neurotrophic properties and can protect neurons against glutamate-induced apoptosis. We report here that GLP-1 can reduce the levels of amyloid-beta peptide (Abeta) in the brain in vivo and can reduce levels of amyloid precursor protein (APP) in cultured neuronal cells. Moreover, GLP-1 and exendin-4 protect cultured hippocampal neurons against death induced by Abeta and iron, an oxidative insult. Collectively, these data suggest that GLP-1 can modify APP processing and protect against oxidative injury, two actions that suggest a novel therapeutic target for intervention in Alzheimer's disease.
Copyright 2003 Wiley-Liss, Inc.
MeSH terms
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / metabolism
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Alzheimer Disease / physiopathology
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Amyloid beta-Peptides / biosynthesis
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Amyloid beta-Peptides / drug effects
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Peptides / pharmacology
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Amyloid beta-Protein Precursor / drug effects
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Cell Death / drug effects*
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Cell Death / physiology
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Exenatide
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Fetus
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Glucagon / pharmacology*
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Glucagon / therapeutic use
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Glucagon-Like Peptide 1
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Hippocampus / drug effects*
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Hippocampus / metabolism
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Hippocampus / physiopathology
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Iron / metabolism
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Iron / pharmacology
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Male
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Mice
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Mice, Inbred Strains
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Neurons / drug effects*
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Neurons / metabolism
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Neurons / pathology
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Neuroprotective Agents / pharmacology*
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Neuroprotective Agents / therapeutic use
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Oxidative Stress / drug effects
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Oxidative Stress / physiology
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PC12 Cells
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Peptide Fragments / biosynthesis
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Peptide Fragments / drug effects
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Peptide Fragments / pharmacology*
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Peptide Fragments / therapeutic use
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Peptides / pharmacology
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Peptides / therapeutic use
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Protein Precursors / pharmacology*
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Protein Precursors / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Venoms*
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Neuroprotective Agents
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Peptide Fragments
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Peptides
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Protein Precursors
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Venoms
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amyloid beta-protein (1-40)
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Glucagon-Like Peptide 1
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Glucagon
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Exenatide
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Iron