The glucagon-like peptides: a new genre in therapeutic targets for intervention in Alzheimer's disease.
Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an insulinotropic hormone, secreted from the enteroendocrine L cells of the intestinal tract in response to nutrient ingestion. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion, and lowers blood glucose 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. The chemoarchitecture of receptor distribution in the brain correlates well with a central role for GLP-1 in the regulation of food intake and response to aversive stress. We have recently reported that GLP-1 and several longer acting analogs that bind at the GLP-1 receptor, possess neurotrophic properties, and offer protection against glutamate-induced apoptosis and oxidative injury in cultured neuronal cells. Furthermore, GLP-1 can modify processing of the amyloid beta- protein precursor in cell culture and dose-dependently reduces amyloid beta-peptide levels in the brain in vivo. As such, this review discusses the known role of GLP-1 within the central nervous system, and considers the potential of GLP-1 and analogs as novel therapeutic targets for intervention in Alzheimer's disease (AD) and potentially other central and peripheral neurodegenerative conditions.
Perry
TracyAnn
T
Laboratory of Neuroscience, Section of Drug Design & Development, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. perryt@grc.nih.gov
Greig
Nigel H
NH
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000502:physiology / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000502:physiology / Q000627:therapeutic use*; D011498:Protein Precursors / Q000502:physiology / Q000627:therapeutic use*; D018027:Receptors, Glucagon / Q000819:agonists / Q000187:drug effects / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011498:Protein Precursors; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D005934:Glucagon