A new Alzheimer's disease interventive strategy: GLP-1.
Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an endogenous 30-amino acid gut peptide, which binds at the GLP-1 receptor coupled to the cyclic AMP second messenger pathway. GLP-1 receptor stimulation enhances pancreatic islet beta-cell proliferation, glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. Not limited to the pancreas, the chemoarchitecture of GLP-1 receptor distribution in the brain of rodents and humans correlates with a central role for GLP-1 in the regulation of food intake. However emerging evidence suggests that stimulation of neuronal GLP-1 receptors plays an important role in regulating neuronal plasticity and cell survival. GLP-1 has been documented to induce neurite outgrowth and to protect against excitotoxic cell death and oxidative injury in cultured neuronal cells. Moreover, GLP-1 and exendin-4, a naturally occurring more stable analogue of GLP-1 that likewise binds at the GLP-1 receptor, were shown to reduce endogenous levels of amyloid-beta peptide (Abeta) in mouse brain and to reduce levels of beta-amyloid precursor protein (betaAPP) in neurons. Collectively these data suggest that treatment with GLP-1 or a related peptide beneficially affects a number of the therapeutic targets associated with Alzheimer's disease (AD). Although much remains to be elucidated with regards to the downstream signaling pathways involved in the pro-survival properties of GLP-1, modulation of calcium homeostasis may be critical. This review will consider the potential therapeutic relevance of GLP-1 to CNS disorders, such as AD.
Drug Design & Development Section, Laboratory of Neurosciences, Gerontology Research Center, Intramural Research Program National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. perryt@grc.nia.nih.gov
Tracy Ann
TA
Perry
Nigel H
NH
Greig
D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D005934:Glucagon / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology*; D052216:Glucagon-Like Peptide 1; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology*; D011498:Protein Precursors / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D010446:Peptide Fragments; D011498:Protein Precursors; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D002118:Calcium