Studies in a mouse model of Alzheimer’s disease (AD) have shown how a drug that was originally developed to treat diabetes demonstrates what researchers in the U.K. and China call “clear promise” as a treatment for AD and other neurodegenerative disorders in humans. The studies, led by Christian Hölscher, Ph.D., at the U.K.’s Lancaster University, confirmed that AD mice treated using a triple-receptor agonist (TA) showed “significantly reversed memory loss,” as well as reduced neuroinflammation and oxidative stress, lower amyloid plaque load in the brain, and increased levels of brain-derived neurotropic factor (BDNF), a key growth factor that protects synaptic function.
“…these findings show that novel TAs are a promising lead for the design of future treatment strategies in AD,” the researchers write in their published paper in Brain Research, which is entitled “Neuroprotective Effects of a Triple GLP-1/GIP/Glucagon Receptor Agonist in the APP/PS1 Transgenic Mouse Model of Alzheimer’s Disease.”
Type 2 diabetes mellitus (T2DM) is a known risk factor for AD, and this association has motivated scientists to investigate whether antidiabetic drugs might also be effective against AD. Studies have shown that the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which have antidiabetic properties, can play a neuroprotective role in the brain and have demonstrated promising effects in animal models of AD.
Prof. Holscher’s team turned to a triple-receptor agonist that activates GIP-1, GIP, and glucagon receptors. The drug had previously been in development for treating diabetes, but hadn’t been assessed for any neuroprotective properties. They tested the drug in a mouse model of AD that demonstrates hallmark symptoms of AD, including memory loss, chronic brain inflammation, amyloid plaque formation, synaptic loss, and reduction in synaptic plasticity.
The results showed that a daily injection of TA reversed memory loss in AD mice, which was assessed in a spatial water maze test. The drug also reduced levels of the mitochondrial proapoptotic signaling molecule BAX, increased the antiapoptotic signaling molecule Bcl-2, and boosted levels of BDNF. Levels of synaptophysin were also elevated, which the researchers say demonstrates protection against the synaptic loss that is seen in AD. Interestingly, their previous work had indicated that GLP-1 and GIP analogs protect synapses from amyloid-induced stress and keep them functioning.
“Furthermore, TA treatment reduced the total amount of β-amyloid, reduced neuroinflammation (activated microglia and astrocytes), and oxidative stress in the cortex and hippocampus,” the authors write. “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.”
Given the “impressive” preclinical data demonstrating the neuroprotective properties of GLP-1, GIP, and glucagon receptor agonists, clinical trials are now under way to investigate the neuroprotective effects of the GLP-1 receptor agonists extendin-4 (Byetta®, Bydureon®) and liraglutide (Victoza®) in patients with AD or with Parkinson’s disease, the authors note. “A pilot study testing the GLP-1 analogue liraglutide in AD patients showed promising results.”
The researchers acknowledge that further dose–response tests will be needed, as well as direct comparisons with other drugs, to determine whether the new TA is more effective against neurodegnerative disorders than prevously developed drugs. Nevertheless, they conclude, “The novel triple GLP-1/GIP/Gcg receptor agonist holds clear promise of being developed into a new treatment for chronic neurodegenerative disorders such as Alzheimer’s disease.”