Research reportNeuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer's disease
Introduction
Alzheimer’s disease (AD), is a progressive neurodegenerative disease, characterized clinically by progressive memory loss, cognitive decline, and aberrant behavior [1]. Currently, there is no treatment can improve this condition. Epidemiological studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD) (Luchsinger et al., 2004, Ohara et al., 2011). The underlying mechanism is most likely that insulin signaling is impaired in the brains of AD patients (Moloney et al., 2010, Talbot et al., 2012). This motivated research in drugs that have shown good effects in treating diabetes to investigate if they could be helpful in treating AD as well. Previous studies have shown that the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can play a neuroprotective role in the brain and show very promising effects in animal models of AD (Duffy and Holscher, 2013, Faivre and Holscher, 2013b, Li et al., 2010, McClean et al., 2011, McClean and Holscher, 2014). Glucagon (Gcg) is a hormone and growth-factor, and the Gcg receptor is expressed in the brain (Hoosein and Gurd, 1984, Mayo et al., 2003). Activation of the receptor can activate neuronal activity and cellular Ca2+ signaling and may have neuroprotective properties (Ayush et al., 2015). Here we test the effects of a triple receptor agonist (TA), which activates GIP-1, GIP and glucagon receptors at the same time. This novel drug has been developed as a potential treatment for diabetes (Finan et al., 2015). No studies have been published that test the neuroprotective effects of this novel drug. We therefore tested this promising TA in the APPSWE/PS1dE9 mouse model of AD. This mouse model recapitulates some of the hallmarks of AD, such as memory loss, synaptic loss, reduction of synaptic plasticity, reduction of neurogenesis in the dentate gyrus, chronic inflammation in the brain, and formation of amyloid plaques in the brain (Duffy and Holscher, 2013, Goto et al., 2008, Hamilton et al., 2011, Hamilton and Holscher, 2012, McClean et al., 2011). We tested the effects of TA in this transgenic mouse model and evaluated the neuroprotective effects. We analyzed memory formation, hippocampal neurogenesis, the expression levels of Brain Derived Neurotrophic Factor (BDNF) (Blurton-Jones et al., 2009), mitochondrial apoptosis signaling proteins, neuroinflammation and oxidative stress levels.
Section snippets
TA-treatment improved the learning and memory impairment of APP/PS1 mice in the water maze
A two-way ANOVA found a significant difference between groups (p < 0.0001) and over time (p < 0.001). In the Morris water test, it was observed that the control mice, APP/PS1 mice and TA-treated APP/PS1 mice had a similar escape latency (P > 0.05). On day 5, the average escape distance in searching for the hidden platform in the APP/PS1 mice was significantly longer than that in the control mice (P < 0.05). Compared to the APP/PS1 group, the TA-treated APP/PS1 group’s average escape distance
Discussion
The results demonstrate for the first time that the novel GLP-1/GIP/Gcg receptor agonist has clear neuroprotective effects in the APP/PS1 mouse model of AD. Memory formation in the spatial water maze task was improved by the drug, and the amyloid plaque load in the cortex and hippocampus was reduced. This result confirms our previous findings that single GLP-1 or GIP analogues can protect from memory loss in this mouse model of AD (Faivre and Holscher, 2013a, Faivre and Holscher, 2013b, McClean
Peptide and chemicals
The triple GLP-1/GIP/Gcg used in this study was synthesized by China Peptides Co, Ltd. (Shanghai, China) to 95% purity. The identity and purity of the peptide was confirmed by reversed-phase HPLC and characterized using matrix assisted laser resorption/ionization time of flight (MALDI–TOF) mass spectrometry. The peptide was stored in dry form and dissolved in double-distilled water containing 0.9% NaCl2 before experiments. A Bi-cinchoninicacid (BCA) protein assay kit was purchased from Apply
Contributors
JT, WL and YL conducted the experiments, LL and CH conceived the experiment and wrote the manuscript.
Acknowledgements
This work was funded by the Ministry of Human Resources and Social Security, Shanxi Province [(2010)255], by a Shanxi Scholarship Council of China, and supported by a grant from the Alzheimer Society UK. The authors declare no conflict of interest
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