Cobbers on the Brain

If you are active on social media, or watch the news, you may be familiar with a fundraiser known as The ALS Ice Bucket Challenge. The challenge involves dumping a bucket of ice water over your head to promote awareness for ALS. The other part of the challenge involves nominating another to complete the challenge and encourages the participants to donate money to ALS if they don’t complete the challenge in 24 hours. According to the ALS Association, the ice bucket challenge raised 115 million dollars in a six week period from August to mid-September of 2014. The ALS Ice Bucket Challenge was such a success, that the Association made it an annual event, and will continue the tradition until a cure is found.
Despite the large sum of money raised and the obvious increase in awareness for the disease, there are many who still may not know what ALS is. ALS, also known as Amyotrophic Lateral Sclerosis or Lou Gehrig’s Disease, is a neurodegenerative disease that affects neurons in the central nervous system. Motor neurons flow from the brain, through the spinal cord and out to the muscles of the body. In patients with ALS, motor neurons progressively lose their ability to function, eliminating the brains capacity to control muscle movement. As the disease progresses, the affected muscles waste away as they lose their ability to contract. The disease eventually takes away the ability to walk, write, speak, breathe and eat, and in the latter stages of the disease patients can become completely paralyzed. Due to the debilitating nature of the disease, the typical lifespan of someone with the disease is 2-5 years, averaging 3 years. Around 1 in 50,000 people will be diagnosed with ALS, and in the U.S. alone, around 6,400 people are diagnosed every year.¹
Some of the leading thoughts on the causes of ALS are glutamate toxicity and protein aggregates. Glutamate is an excitatory neurotransmitter, and when it binds to its receptor it causes an influx of calcium into the neuron (too much calcium can cause the cell to die). Another cause that is being explored, is protein aggregates. Protein aggregates consist of misfolded proteins that accumulate within the cell eventually leading to cell death.² Both disrupt the cells ability to function normally and are believed to contribute to the death of motor neurons in patients with ALS.
I hope you were able to learn something new about ALS, so next time you are nominated for the Ice Bucket Challenge you can share some of what you learned to help raise awareness for the disease.

1. ALS Association website http://www.alsa.org/about-als/what-is-als.html
2. http://dx.doi.org/10.1016/j.bbadis.2012.11.013

It is interesting to think that a single molecule can be a similar variable in a handful of diverse and devastating diseases. It is even more interesting to think that this same molecule is necessary for the control of inflammatory processes in the body. The molecule I am referring to is Nitric Oxide (NO), and it is the main topic of conversation this week in my neurochemistry class. We talked about it in the context of inflammation and a number of other neurodegenerative diseases. I would like to begin by explaining the inflammatory process and why it is important in the body.
The inflammatory response is a process that developed in higher organisms as a mechanism of defense against pathogens and invaders. The response completes a number of tasks:

• It rounds up the necessary cellular components to help manage the cellular damage
• The components localize and eliminate the pathogen or injury-causing stimuli
• Damaged tissue components are removed
• Tissue reconstruction is initiated

In summary, the inflammatory response is necessary for cellular damage to stop and for the body to begin to heal. However, constant or excess inflammation can be extremely harmful to the body, and in particular, the brain. This is why NO is important. It is the molecule that regulates the inflammatory response in the brain. This shows that low levels of it are necessary for proper brain functioning and inflammatory responses.
So, this is why NO needs to be somewhat present in the body. On the other hand, we also discussed the many neurodegenerative diseases that are caused by excess NO. They include:

• Periventricular leukomalacia (PVL)
• Krabbe’s disease
• X-linked adrenoleukodystrophy
• Multiple sclerosis (MS)

In each of these diseases the gene transcribing NO, the iNOS gene, is upregulated. Genes are upregulated by the activation of molecules called transcription factors. The most important one in the upregulation of the iNOS gene is NF-kB. Normally NF-kB is inhibited by being bound to another molecule; however, when it becomes uninhibited it moves into the nucleus to transcribe iNOS. The over transcription of iNOS is the main factor affecting the pathogenesis of these diseases. Furthermore, it is the connecting factor. Each of these diseases is thought to be an imbalance of NO in the brain leading to neurodegeneration.
 
While all of the diseases produce strikingly different symptoms and signs, it has been found that the underlying neurochemistry has at least one common link, nitric oxide. It has also been found that NO is needed to a certain extent in order to regulate the natural inflammatory response. However, too much of it is harmful and can lead to many different diseases. These conclusions are where research is currently stuck. We are left to determine the correct amount of NO necessary for proper brain function, not too much and not too little. The production of NO by the iNOS gene is a delicate balancing act that can easily fall to one side or the other.

As a relatively healthy person, insulin is something that I rarely consider, I do not consider how my intake of sugar may affect my body, I also do not consider what would happen if I did not have the necessary insulin in my body.  Insulin is involved in many processes in the body, more than I have ever really considered. Deficiencies in insulin lead to diabetes, and in turn obesity, but also with links to Alzheimer’s disease.  Insulin is highly involved in metabolic as well as cognitive regulations.  Thus, when the insulin pathway is not working properly, the brain and energy homeostasis are thrown off.  Insulin is the key player in glucose homeostasis, meaning it is the thing that keeps our body’s sugar and energy levels under control.  In the central nervous system, insulin is largely found, but in patients with diabetes or Alzheimer’s disease, there are lower levels of insulin or insulin receptors.  Thus, we see a link of insulin to Alzheimer’s disease (which makes sense as insulin has a part in cognitive part of the brain, especially in learning and memory).  We also can see a link to obesity when insulin is not functioning properly.  This change in food intake is changed as within the insulin signaling pathway, we see the PI3-K pathway, which when activated will send signals for decrease of food intake.  The neurons that are involved in this regulation of food intake are the AgRP/NPY neuron (which tells the body to eat more) and the POMC neuron (which sends the signals that the body is full) and if insulin is not functioning fully, then there is excess glucose, leading to these two neurons getting signals screwed up. Thus, if the insulin is not working properly, then there is no signal to decrease food intake, which will then lead to over ingestion and set the body up for obesity.  Another interesting part of these neurons is that in a high fat diet, the POMC neuron is tricked, and instead of recognizing high fat food as something that should satiate our bodies, it instead still thinks we are hungry (in the figure below we see this pathway and that fatty food cause the same pathway as hunger).

 
It really took me by surprise learning that this is why it is so easy to eat lots of fatty foods without ever really feeling full, and explains why problems with insulin can lead to obesity.
The other pathway that insulin signals through is the MAP-K cascade, which is involved in cognition (especially learning and memory).  Thus, we can see how Alzheimer’s disease has a link to poor insulin function, as there would be decreased memory when there is less signaling coming from the insulin pathway. In addition to causing the memory issues, the PI3-K pathway (from insulin pathway) causes a descrease in phosphorylated tau, so as PI3K stops functioning appropriately, phosphorylated tau increases, which is a large player in AD.  In addition to the tau, we see an increase in Aβ plaques, which inhibits the insulin pathway, thus causing loss of the cognition that is gained. I find it extremely interesting that AD is linked to insulin.  It is not something that I had ever considered to be related to each other.  I also found myself wondering if having diabetes earlier on would pretty much mean that one will end up with AD or if there are ways to prevent AD when someone has type II diabetes. It is kind of a foreboding thought, just because a large possibility for the future of people who have this type of diabetes is AD, which is a scary thought to know that you will slowly forget who you are.  However, I think it is interesting that we have found such a link, and how insulin may be the link in curing AD as effectively as it is in helping with diabetes. All in all, I found that I really should put more thought towards how insulin is working in my body and how what I may be eating may hurt the insulin or its receptors. What I am trying to get across is that insulin plays such a crucial role in our lives, and that maybe we should consider how to keep the insulin in our body functioning appropriately (by eating healthy) so we don’t have to be worried about whether our sugar will be metabolized and our body will function properly in the future.