Of all the neurodegenerative diseases, Alzheimer’s disease (AD) stands as the most common worldwide. While the onset is complex in nature, a hallmark sign of illness is the accumulation of a particular peptide in the brain, known as amyloid beta (Aβ) (http://www.jci.org/articles/view/25100). When present, the molecule can aggregate to form plaques and also interact with cells in the brain leading to altered signalling and function.
One particular devastating interaction occurs between Aβ and metabotropic glutamate receptor 5 (mGluR5). This molecule normally interacts with glutamate to modulate calcium oscillations (http://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.1997.69041467.x/abstract) during normal cell signalling. However, the same effect can be stimulated by Aβ leading to significant loss of calcium and alter the function of these cells. As the levels of Aβ increase, so does the potential for greater damage to overall neurological function.
Potential avenues for treatment via mGluR5 have been examined for several years. One particular treatment option is 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl) pyridine (CTEP). This molecule possesses a high affinity for the receptor and acts as an inhibitor of activity http://jpet.aspetjournals.org/content/339/2/474.long . This molecule has already been examined in mice as a possible treatment in fragile X syndrome (http://www.cell.com/neuron/fulltext/S0896-6273(12)00272-3) and major depressive disorder (http://jpet.aspetjournals.org/content/353/1/213.full). In both these cases, administration has shown significant benefit.
As a result of the positive results from treatment, a team of researchers led by Stephen Ferguson at the University of Ottawa wanted to find out whether CTEP could be useful in helping to treat Alzheimer’s disease. They published their findings earlier this year in Cell Reports (http://www.cell.com/cell-reports/fulltext/S2211-1247(16)30522-8). Based on the results, the inhibition of the interaction between Aβ and mGluR5 may offer a possible route for treatment to slow down the disease.
The group worked with two different mouse models possessing the capability of developing conditions similar to Alzheimer’s Disease. The team waited for the animals to reach nine months of age such that they would be well into the developmental phase of the disease and have significant amounts of Aβ. (background on the mouse strains http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756084/ & http://www.jneurosci.org/content/27/26/7006.full).
The mice were given CTEP by abdominal injection every other day over the course of 3 months and were observed in the hopes of seeing behavioural improvement. They did. The drug was working just as the group hoped. This finding suggested CTEP was most likely helping to slow the degenerative process and when used over the long term could possibly ameliorate the prognosis.
The next step was to identify exactly how CTEP was accomplishing this task at the cellular level. The authors expected to see healthier brain tissue as a result of chronic treatment. They did. However, what was somewhat surprising was the apparent reduction in the amount of Aβ in comparison to controls. Somehow, the molecule had not only inhibited the interaction with mGluR5, but also had led to a decrease in the amount of the amyloid peptide.
The results of the study clearly show the potential benefit of CTEP in AD and offer an unexpected benefit worth investigating further. Due to the reduction of Aβ in mice chronically treated with the drug, the authors suggest a possible direct involvement of mGluR5 in the formation of toxic amyloid peptides. While this may be the case, the mechanism behind this theory remains unknown and requires further study.
While promising, this study does represent only a model and as such cannot be directly extrapolated to humans. It will be years before CTEP reaches clinical trials though the road may be less bumpy should this time comes. This is because an analogue of this molecule, known as Basmiglurant, is already in phase II clinical trials. The experience with this particular drug may pave the way for CTEP to receive a smoother ride moving forward.
Article by Jason Tetro, CAN advocacy officer
