Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron.
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.
Perry
TracyAnn
T
Section of Drug Design and Development, Laboratory of Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. perryt@grc.nia.nih.gov
Lahiri
Debomoy K
DK
Sambamurti
Kumar
K
Chen
Demao
D
Mattson
Mark P
MP
Egan
Josephine M
JM
Greig
Nigel H
NH
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D000077270:Exenatide; D005333:Fetus; D005934:Glucagon / Q000494:pharmacology* / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007501:Iron / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000096:biosynthesis / Q000187:drug effects / Q000494:pharmacology* / Q000627:therapeutic use; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D011498:Protein Precursors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014688:Venoms
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D014688:Venoms; C078592:amyloid beta-protein (1-40); D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide; D007501:Iron