This first week of 2018 has seen a fair amount of buzz in the media over a study published in October showing memory improvement in mice given a novel drug that targets receptors for hormones with anti-diabetic properties.  I brewed some coffee and sat down with a highlighter.

Simple Summary

Mice bred to develop Alzheimer’s-like symptoms were given a drug that increased sensitivity to hormones shown to combat diabetes.  The mice showed memory improvement to near normal levels.

More Detail

Previous studies have shown success with reversing memory loss in animal models of Alzheimer’s by stimulating one and then two receptors in the brain for hormones associated with anti-diabetic properties.  The authors of this study Neuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer’s disease wanted to see if they could improve upon those results by targeting an additional hormone receptor.  They chose a drug called a triple receptor agonist (TA) because it stimulates three different receptors simultaneously.  The drug was originally intended as a potential treatment for diabetes.

The study was a classic model using three groups for comparison.  A control group of normal mice and two groups of transgenic mice bred to develop Alzheimer’s-like symptoms of neurodegeneration, cognitive impairment, chronic inflammation, amyloid plaques in the brain, and memory loss.  One group of transgenic mice was untreated and the other given a drug that simultaneously activated three different receptors for hormones with anti-diabetic properties.

Researchers used the Morris water test for testing learning and memory .  The mice trained for 5 days learning the location of the hidden platform.  On day 6 the platform was removed and the groups were compared to see how much time each group spent in the correct quadrant.

The mouse brains were analysed for beta amyloid plaque load in the cortex and hippocampus, immune response (inflammation) in the cortex and hippocampus, and oxidative stress levels in the cortex and hippocampus.

In all measures the control group scored best, followed by the treated group and lagging a distant 3rd was the untreated group.  While the AT group did not reach the levels of the normal mice, the study did conclusively show that the addition of the triple receptor agonist did have a strong positive effect on the brains of transgenic mice.  The AT group of transgenic mice showed improved learning, memory, and neurogenesis as well as reduced inflammation, amyloid beta plagues, and oxidative stress.  The drug therefore shows promise for treatment of Alzheimer’s.

Author’s note: Interestingly, a dive into the references section of the paper showed human trial success against Parkinson’s using a single receptor agonist.  Given the shared pathologies of Parkinson’s and  Alzheimer’s, these studies point to the importance of insulin signalling not only to diabetes, but to Alzheimer’s and Parkinson’s.  Insulin sensitivity is certainly a focus of the MEND Protocol that is addressed through diet and fasting.

Into The Weeds

Given the correlation between type II diabetes (T2D) and Alzheimer’s, the researchers were interested in furthering studies of hormones associated with anti-diabetic properties that have shown promise in animal models of Alzheimer’s.

Previous studies have looked at glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor stimulation.  This study added Glucagon (Ccg) receptors to the mix.

GIP and GLP-1 decrease blood sugar levels by enhancing the secretion of insulin.  Glucogon, however, is key to the flip side of the insulin process.  When the beta cells of the pancreas detect increasing levels of glucose they begin to produce insulin to lower blood sugar levels.  When the alpha cells of the pancreas detect decreasing levels of glucose they produce glucogon to increase blood sugar levels.  This is a simplified explanation of how blood sugar homeostasis occurs.

It’s not clear how two hormones that promote a decrease in blood sugar plus a hormone that promotes an increase in blood sugar can combine to treat diabetes.  The answer may lie in cAMP synthesis.  The authors state that all three hormones are members of the growth factor family and are associated with cAMP synthesis (cAMP being a derivative of ATP) that has been shown to normalize energy utilization, assist in cell repair, and normalize growth-factor related gene expression.  Furthermore, cAMP and its associated kinases function in several biochemical processes, including the regulation of glycogen, sugar, and lipid metabolism.

So now that one group of mice is “AMPed up”, how was their performance assessed?  The first test was to gauge learning.  During the five days of performing the Morris water test the untreated group spent significantly longer looking for the escape platform.  The longer amount of time spent on day five (the final day of training) as compared to the other two groups indicates that the untreated transgenic mice had more difficulty learning the task.

When the platform was removed from the water test on day six, the untreated group looked lost compared to the other two groups.  A diagram of the swim pattern for each group shows the untreated transgenic mice swimming all over the tank, while the other two groups focused on the area where the platform had been the previous five days.  Sadly, the pattern for the untreated group looks like a map of me wandering around the house looking for my car keys.

The mouse brains were examined using immunohistochemical analysis and 4-HNE was measured to give an indication of lipid peroxidation.  Kind of like looking for smoke to detect a fire.

Measures of mitochondrial apoptosis signals 4-HNE and BAX were reduced in the treated group.  Anti-apoptotic signaling molecules were increased.  These and other measures indicate that neurogenesis in the dentate gyrus (part of the hippocampus) was normalized and synaptic activity numbers and functions were improved in the treated group.

Final Thoughts

Simultaneously activating three “anti-diabetes” receptors improved learning, memory, and physiological brain health in cognitively impaired mice.  The results bolster the idea that diabetes and Alzheimer’s are correlated and also that a multi-pronged approach will likely be needed to combat a disease as complex as Alzheimer’s.