Peptide drugs that have been developed to treat type 2 diabetes show neuroprotective effects

Holscher, Christian (2014) Peptide drugs that have been developed to treat type 2 diabetes show neuroprotective effects. Regulatory Peptides, 192-19. pp. 55-56. ISSN 1873-1686

Abstract

In the paper “Exendin-4 promotes the membrane trafficking of the AMPA receptor GluR1 subunit and ADAM10 in the mouse neocortex” by Ohtake et al. [12] the cellular signalling processes of the incretin hormone Glucagon-like peptide-1 (GLP-1) in neurons are described for the first time. GLP-1 is a hormone and a growth factor that has attracted a lot of interest in the diabetes field as it increases insulin release and glucose uptake. Several GLP-1 analogues have been developed to treat type 2 diabetes. Type 2 diabetes is a risk factor for Alzheimer's disease [6], and insulin signalling in the brains of patients with Alzheimer's disease is impaired [11] and [14]. Exendin-4 (Byetta®) is one of the GLP-1 receptor agonists that are on the market to treat diabetes. In several preclinical studies, this drug has been shown to be neuroprotective in a range of animal models of neurodegenerative diseases, including Alzheimer's and Parkinson's disease [4], [5] and [7]. In fact, a recent pilot clinical trial showed promising effects in patients with Parkinson's disease [1]. In transgenic mouse models of Alzheimer's disease, similar neuroprotective effects were found with the diabetes drug liraglutide (Victoza®), a GLP-1 analogue that is also on the market as a diabetes drug. In mice that overexpress human mutated amyloid precursor protein, the drug reduced amyloid levels and its aggregation into plaques. Also, synapse numbers in the cortex were increased, and memory formation and synaptic plasticity was much improved [9] and [10]. In this paper by Ohtake et al., the authors report for the first time what cellular processes underlie these drug effects. GLP-1 receptor activation enhances gene expression of the synaptic marker PSD95, demonstrating that synapse numbers are boosted by the activation of the associated genes. In addition, expression of the GluR1 subunit of the AMPA receptor is enhanced. The AMPA receptor is important for fast synaptic transmission, and the upregulation explains how GLP-1 signalling not only increases synapse numbers, but also increases synaptic activity and plasticity, and finally memory formation [9]. Furthermore, the cleavage of the amyloid precursor protein is shifted away from the amyloid producing beta-secretase pathway and towards the growth-signalling pathway of the ADAM10 alpha-secretase pathway [3], this may explain why GLP-1 analogues reduce amyloid levels in the brain in some studies [9]. In addition to these central effects, the expression of the growth factor BDNF is enhanced by exendin-4. As this growth factor is important in synapse maintenance and function and shows neuroprotective activity in mouse models of Alzheimer's disease [2], an enhanced expression will add to the neuroprotective effects activated by GLP-1 signalling. While some of the second messenger growth factor signalling cascades that are activated by exendin-4 and liraglutide had been described before [8] and [13], the present paper by Ohtake et al. [12] describe the key signalling pathways and genes that are being activated, and thereby can explain how these drugs reduce biomarkers of Alzheimer's disease in transgenic mice. Both drugs exendin-4 and liraglutide are currently being tested in clinical trials in Alzheimer patients (identifiers NCT01255163 and NCT01843075, respectively), and this paper adds to the understanding of the cellular neuroprotective mechanisms of the drug action and boosts our hope that they may be effective in treating this devastating disease for which there is no cure.