Potential Role of Glucagon-Like Peptide-1 (GLP-1) in Neuroprotection

Abstract

The current understanding of neurodegenerative processes in sporadic diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) or multiple sclerosis is very limited. Several risk factors have been identified that may shed light on the underlying mechanisms that initiate the neurodegeneration. Type 2 diabetes mellitus has been identified as a risk factor for AD and PD. In AD patients, desensitization of insulin receptors in the brain has been shown, even in non-diabetic patients. Insulin acts as a growth factor in the brain and supports neuronal repair, dendritic sprouting and synaptogenesis, and protection from oxidative stress. Importantly, several drugs have been developed to treat type 2 diabetes that re-sensitize insulin receptors and may be of use to prevent neurodegenerative processes. Glucagon-like peptide-1 (GLP-1) is a hormone that facilitates insulin release under high blood sugar conditions. Interestingly, GLP-1 also has very similar growth factor-like properties to insulin, and has been shown to reduce a range of degenerative processes. In pre-clinical studies, GLP-1 and longer-lasting protease-resistant analogues cross the blood-brain barrier, protect memory formation (AD) or motor activity (PD), protect synapses and synaptic functions, enhance neurogenesis, reduce apoptosis, protect neurons from oxidative stress, and reduce plaque formation and the chronic inflammation response in the brains of mouse models of AD, PD, amyotrophic lateral sclerosis, stroke and other degenerative diseases. GLP-1 signalling does not affect blood sugar levels in non-diabetic people and therapies that affect GLP-1 signalling have a good safety profile as shown by the chronic application of drugs currently on the market (liraglutide, Victoza(®); NovoNordisk, Copenhagen, Denmark, and exendin-4, Byetta(®); Amylin, San Diego, CA, USA). Based on the extensive evidence, several clinical trials are currently underway, testing liraglutide and exendin-4 in AD and PD patients. Therefore, GLP-1 analogues show great promise as a novel treatment for AD or other neurodegenerative conditions.