On Glutamergic Excitotoxicity and Preventing Stagnation
Before I tell you about all the new and exciting things I'm learning in the neuron world, I do have to correct something from my last journal. At the time, I was misunderstanding bias (a cause of unintentional error in economic models) to be bias on the part of subjects within the model. It seems however, that economic theory (well, at least Ben Goes) regards error arising from bias to be coming from the creator of the model, not the circumstances or constituents of the model itself. So while human bias wouldn't be a source of error for the model's outcome, it could definitely play a role in causing error during the creation or production of the economic model. I apologize for any confusion this misunderstanding may have caused for anyone.
Nevertheless my brainy friends, let us press onward. Recent publications on Alzheimer's Disease studies have truly been rather captivating.
In January, I wrote a journal about the Trans-neuronal Spread Hypothesis of Alzheimer's Disease pathogenesis. Lo and behold, an article published by Nature's Scientific Reports not too long after I wrote that journal may have just given this theory some headway. Although the original study I explored in my earlier journal focused specifically upon tau proteins and the one I will discuss here did not, they do lend themselves to one another in certain capacities. A collaboration between Canadian and French research teams, this study explored conditions of the prefrontal cortex, specifically Brodmann's Area 9 (BA9), with varying cognitive stages of Alzheimer's diseased brains. As with most clinical research efforts on Alzheimer's Disease, some baseline characteristics such as synaptic loss, neurofibrillary tangles, and plaques were identified as a set of delimiters indicated by the disease's currently ambiguous nature. Cortical samples from 171 patients were extracted and analyzed for glutamergic transmission and its excitotoxicity. Glutamate is an extremely widespread neurotransmitter that is especially common among synapses throughout the prefrontal cortex of the brain. The reason researchers chose this glutamergic component as the subject of assessment is because just like too much amyloid-beta proteins is a bad thing, an excessive glutamergic index at synaptic connections can have adverse effects, hence the term excitotoxicity (toxic levels of neuronal excitement). By studying glutamate levels in cortical samples of Alzheimer's brains at different cognitive stages, researchers were able to determine at what point of the disease's cognitive progression glutamate excitation reached toxic levels.
The synaptic activity of glutamate as a neurotransmitter is determined by a group of 5 amino acids called excitatory amino acid transporters (EAATs) which are primarily coded for as exons in the genetic code of astrocytes (a type of glial cell). So an aside here, this further demonstrates the necessity of glial cells to control and moderate the activity of neurons. Anyway, when these amino acids are produced, the consequent neurons begin to signal to one another through the communication vehicle of glutamate. At every neuronal synapse, we have two receptor areas; presynaptic vesicles (parts of the neuron sending the signal) and postsynaptic vesicles (parts of the neuron receiving the signal). With respect to glutamate, the molecule being released by the presynaptic vesicles is called a Vesicular Glutamate Transporter (VGLUT). Levels of two molecular sub-types (VGLUT1 and VGLUT2) were found to show a severe decline in the cortical samples of Alzheimer's Diseased brains and thus strongly correlated to cognitive deficiencies associated with the disease. Based upon this information, one may assume that there is a decreased level of the neurotransmitter glutamate, meaning the excitotoxicity hypothesis ought to be rejected. But what the study found is indeed quite intriguing. The team discovered that the disease can be regarded in two different stages with respect to glutamate transmission across a synapse. The first stage being marked by extremely high levels of glutamate which leads to excitotoxicity and neuronal degeneration because the buildup disables synaptic activity. The second stage then, is what researchers were initially observing - extremely decreased levels of glutamate. This of course happens due to neuronal inactivity causing the glial cells to cease production of VGLUT1 and VGLUT2. Although it was clearly stated in the article that the sample size of investigation subjects was far too small to confirm that these two stages actually occur in the progression of Alzheimer's Disease, I thought the variety in cognitive stages definitely provided unique insight into the disease's progression.
Of course, the study delved into questions about a variety of other neurotransmitters and biochemical components associated with the neuronal status of brains afflicted with Alzheimer's Disease but for the sake of brevity and you, dear reader's boredom, let's cut to the chase. What does this study on synaptic activity have to do with the transneuronal spread hypothesis and the so-called "Tau infection"? Well first, "The findings of this study suggest that the loss of synaptic markers in BA9 is a late event that is only weakly related to AD dementia." Essentially this means that, contrary to common belief, the progression of Alzheimer's and Dementia are less likely to be determined by neuron and synapse destruction. Rather, more directly positive correlations have been found with respect to synaptic dysfunction and cognitive impairment that come with these diseases of the brain. If you recall, I wrote this statement in my earlier journal "The Tau Infection" - "So theoretically, what was being said is that the amount of tau in an individual neuron depended largely upon the extent of connections it had with other neurons." Similarly, this French-Canadian executed study once again provokes us to think about whether we should be focusing on neurons/isolated components or synapses/interactive neurological connections when attempting to understand a disease such as Alzheimer's. I'm not sure we can venture so far as to group the two studies as both being proponents of the Transneuronal Spread Hypothesis. They are alike however in that they seek to pose a possible redirection of our attention as a collective neuroscientific effort towards possible alternative methods.
And for that, I am certain there is something to be said concerning where one ought to stop when trying to decipher a seemingly impossible enigma. But I will contend; it isn't so large of an issue that one neurological approach is yielding few results. Rather, the more dangerous issue arises when questions are not being asked about this obvious lack of efficacy. We must remember that any study, any endeavor to solve any problem, both small and large, is a collaborative effort. Why do you suppose there are so many different theories on how Alzheimer's even begins to afflict someone's brain? It's because each person thinks very differently than the other person sitting beside them. It is advantageous therefore to take stock of this diversity in thought. For without such, we would have likely been entranced by one, incomplete theory and thus entranced by stagnation that arises from an absence of questioning.