So first, what exactly is a ganglioside? A ganglioside is a complex lipid that is found in the grey matter of a human brain. These lipids are found to play a major role in brain function, and development, as well as with ‘brain remodeling’ later in a persons life. Seeing as gangliosides are important for brain activity and retention of synaptic plasticity, it only makes sense that an improper regulation of them can cause problems, and it does.
Take for example, in the development of Alzheimer’s, and β amyloid plaques. If the ganglioside GM1 becomes clustered in a plasma membrane microdomain, it can undergo a conformational change and become a binding site for these Aβ oligomers, further promoting aggregation of AβO’s into synaptoxic Aβ plaques. While that is somewhat understood for the ganglioside GM1, an accelerated degradation of the ganglioside GM2 can actually reduce the binding of Aβ on GM1, and is capable of rescuing the cognitive decline caused by GM1 and the Aβ plaques.
Interestingly enough, an unexpected enemy may be at work relating to the modulation of these gangliosides. Diabetes is shown to accelerate the development of these plaques as well as promote the accumulation of the GM1 clusters themselves and in turn, Aβ aggregates. Additionally, there are thoughts that Aβ can be the catalyst behind insulin resistance via interference in the ganglioside metabolism. This interference can cause an increase in GM3 in the plasma membrane, which fits in with another finding that high GM3 results in insulin resistance as well.
For a link between ganglioside regulation and diabetes itself at the surface level, we need to look no further than a dinner plate. A healthy diet we already know is key to not develop diabetes in many people, however it is believed that ganglioside expression in tissues is affected by deficiencies in nutrients, or in foods that do not provide ganglioside synthesis components. For example, breast milk is a very rich source of sialic acid, which happens to be a building block to a major ganglioside in terms of brain development, GM3. Infants who are not breast fed, have a much lower ganglioside content in the frontal cortex of the brain than their breast fed counterparts.
In the end, there is a dualistic relationship between these diseases, and after further research, it is clear the co-morbidity is by no means unrelated. The same plaques that are the hallmark of Alzheimer’s disease have the capability to trigger insulin resistance through both the inhibition of the IR/S to mTOR pathways, as well as via activation of the TNF-alpha receptor which leads to inflammation. On the flip side, as stated above, insulin resistance and diabetes can accelerate the accumulation of GM1 clusters, and in turn the accelerated accumulation of Aβ oligomers into Aβ plaques. The connections between these two diseases are a connection I never had expected to see, and in the future, it’s intriguing to think about how two “unrelated” diseases may be “causes” of each other in the future.
