Neuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer's disease.

Abstract

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD). Previous studies have shown that the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) that have anti-diabetic properties show very promising effects in animal models of AD. Glucagon (Gcg) is a hormone and growth-factor, and the Gcg receptor is expressed in the brain. Here we test the effects of a triple receptor agonist (TA), which activates GIP-1, GIP and glucagon receptors at the same time. In the present study, the effects of the TA were evaluated in the APP/PS1 transgenic mouse model of AD. The TA was injected once-daily (10 nmol/kg i.p.) for two months. The results showed that treatment with TA significantly reversed the memory deficit in the APP/PS1 mice in a spatial water maze test. Moreover, the drug reduced levels of the mitochondrial pro-apoptotic signaling molecule BAX, increased the anti-apoptotic signaling molecule Bcl-2 and enhanced the levels of BDNF, a key growth factor that protects synaptic function. Levels of synaptophysin were enhanced, demonstrating protection from synaptic loss that is observed in AD. Neurogenesis in the dentate gyrus was furthermore enhanced as shown in the increase of doublecortin positive cells. Furthermore, TA treatment reduced the total amount of β-amyloid, reduced neuroinflammation (activated microglia and astrocytes), and oxidative stress in the cortex and hippocampus. Thus, these findings show that novel TAs are a promising lead for the design of future treatment strategies in AD.

• Authors: Jingjing Tai, Weizhen Liu, Yanwei Li, Lin Li, Christian Hölscher
• Journal: Brain research (Brain Res) Vol. 1678 Pg. 64-74 (Jan 01 2018) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 29050859 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Amyloid beta-Protein Precursor
• Glucagon-Like Peptide-1 Receptor
• Neuroprotective Agents
• Presenilin-1
• Receptors, Gastrointestinal Hormone
• Receptors, Glucagon
• Glucagon-Like Peptide 1
• Glucagon
• gastric inhibitory polypeptide receptor

Topics

• Alzheimer Disease (drug therapy, physiopathology)
• Amyloid beta-Protein Precursor (metabolism)
• Animals
• Disease Models, Animal
• Glucagon (pharmacology)
• Glucagon-Like Peptide 1 (pharmacology)
• Glucagon-Like Peptide-1 Receptor (agonists, metabolism)
• Hippocampus (metabolism)
• Memory Disorders (drug therapy)
• Mice
• Mice, Transgenic
• Neuroprotective Agents (metabolism, pharmacology)
• Plaque, Amyloid (drug therapy)
• Presenilin-1 (metabolism)
• Receptors, Gastrointestinal Hormone (agonists, metabolism)
• Receptors, Glucagon (agonists, metabolism)