Authors: Perry, TracyAnn¹; Greig, Nigel H.²

Source: Current Alzheimer Research, Volume 2, Number 3, July 2005 , pp. 377-385(9)

Publisher: Bentham Science Publishers

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 -cell proliferation, glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. GLP-1 receptors, are coupled to the cyclic AMP second messenger pathway, and are expressed throughout the brain of rodents and humans. We previously reported that GLP-1 and exendin-4, a naturally occurring, long-acting analogue of GLP-1 that binds the GLP-1 receptor (GLP-1R), possess neurotrophic properties. GLP-1R agonists protect neurons against amyloid- peptide (A) and glutamate-induced apoptosis in cell culture studies and attenuate cholinergic neuron atrophy in the basal forebrain of the rat following an excitotoxic lesion. The biochemical cascades activated by neural GLP-1R stimulation are discussed in comparison to those activated by pancreatic receptors, and, additionally, are compared to signaling pathways associated with the classical neurotrophins. GLP-1R stimulation promotes pathways that favour cell survival over apoptosis. GLP-1 readily enters brain, and its diverse physiological actions, which include insulinotropic, cardiovascular as well as neurotrophic ones, may prove beneficial in a variety of diseases prevalent in aging, including Alzheimer's disease (AD). Its ability to lower brain levels of A in mice would appear to be particularly pertinent in this regard. Furthermore, the ready availability of clinical material and the clinical history of its long term use in subjects with type 2 diabetes would support testing the value of GLP-1R agonists in AD trials.

Keywords: insulinotropic peptide; apoptosis; dipeptidyl peptidase(dpp); hippocampus; diabetes; synaptic loss; neurofibrillary; nerve growth factor (ngf)

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1567205054367892

Affiliations: 1: 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. 2: 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.

Publication date: 2005-07-01

More about this publication?

• Current Alzheimer Research publishes peer-reviewed frontier review and research articles on all areas of Alzheimer's disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer's disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer's disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer's disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer's disease. Current Alzheimer Research provides a comprehensive 'bird's-eye view' of the current state of Alzheimer's research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.

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