Cobbers on the Brain

What should insulin be doing?

You’ve probably heard of insulin before but role does it actual play in our bodies? When functioning normally, insulin helps regulate our blood sugar levels by breaking down carbohydrates into different pieces. One of those pieces is glucose which is our bodies main form of energy. Once this glucose is in our bloodstream, the pancreas starts producing insulin which lets glucose into our body’s cells to give them energy. Your body can also store this insulin in muscles, fat cells and liver to be used later if needed.

What does it do in Alzheimer’s Disease (AD)?

Insulin has also been found to protective of the neurons in our brain making it important for cognition, something we know is implicated in AD! The brain is an insulin sensitive organ and insulin has been found to promote memory functioning within it. So, if there is an issue with insulin, there can be an issue with memory and cognition.

What does it do in Type 2 Diabetes (T2D)?

Insulin is most usually talked about in the context of Type 2 Diabetes. With this condition, glucose levels keep rising because the insulin is not moving the glucose into our cells effectively. It’s not that those with Type 2 Diabetes don’t have insulin, they just usually are not using it effectively or don’t produce enough, insulin resistance and insulin deficiency, respectively.

So… how are they connected??

There appears to be a connection between Type 2 Diabetes and Alzheimer’s as patients who develop one are more likely to develop the other. This means if you get Alzheimer’s, your chances of getting T2D are higher than the rest of the population.

Maybe brain inflammation?

When researchers look at the brains of those with Alzheimer’s they find evidence of issues with insulin signaling. A proposed link between the two is the inflammation that occurs when there is a fat accumulation seen in the body in T2D or the sustained inflammation seen in Alzheimer’s brains. It suggested that this inflammation could be due to a specific inflammatory cytokine called TNF-a that induces insulin resistance.

Maybe gangliosides promote insulin resistance?

   AD is characterized by a plaque build-up on the neuronal level referred to as amyloid beta plaques. When these plaques start to build up, a number of other cells cannot perform their usual functions or jobs, dysregulating a lot of other pathways. A ganglioside called GM3 is important in cell metabolism and it’s possible that when these plaques build up, the GM3 cannot do its job and so the downstream signal is blocked leading to insulin resistance.

Could be mTOR deregulation? The evaluation of mTOR can lead to insulin resistance.

 Could be issues with PTP1B?  Elevated PTP1B is found in T2D and could regulate neuronal inflammation.

 What now?

It’s clear we won’t have all the information about the pathology of either AD or T2D nor do we understand fully the connections between the two. In this short post, I have only scratched the surface of the depth of these potential connections but it’s difficult to determine what causes what. Does inflammation cause a build of plaques, or vice versa? Which comes first? Does the mTOR pathway affect the amyloid beta plaques? We know a number of these things are connected but we don’t know where to start in the pathway. More research on these factors could break open the treatment options for AD and T2D- we just need to figure out where to begin.

https://www.mayoclinic.org/diseases-conditions/diabetes/in-depth/diabetes-treatment/art-20044084

Do you know, or have you ever known, someone with Alzheimer’s in your life? At the moment, your answer to this question may or may not be yes, but as time passes it will become more and more likely for all of us to know someone: It is estimated that approximately 5.5 million Americans currently suffer from dementia caused by Alzheimer’s, but worldwide this number is more likely to be around 36 million people. Experts predict this number to reach 115 million by 2050 if no effective treatments are developed. 

So what exactly is Alzheimer’s Disease (AD)?

In one sentence, it is a progressive neurodegenerative disease that causes dementia. This means it is a disease in which the state of different parts of the brain continuously worsen, ultimately leading to a variety of symptoms, some of which include:

1. Memory loss,
2. A lesser ability to function, and 
3. Worsened judgement. 

The most common symptom listed above is forgetfulness. It is usually less noticeable at first, but throughout the course of the disease becomes increasingly worse until even simple daily chores and activities are impossible to manage without some form of help from a caregiver or family member. What many people do not seem to realize, however, is that Alzheimer’s at its later stages has further characteristics that can affect an individual’s personality: 

1. Agitation, 
2. Withdrawal, 
3. Restlessness, and/ or
4. A loss of language skills. 

Therefore, it is increasingly difficult for affected individuals to be cared for in their home, and often move to nursing homes as the disease progresses.  

For many years, researchers have been trying to describe the etiology of Alzheimer’s and pinpoint its specific cause to develop a treatment, or at least improve therapies to slow the progression. Some of the basic science is described below…

Science Behind the Disease

This TED-Ed video gives a brief overview of the basic molecular science and the disease’s progression throughout the brain, which can be directly related to the visible symptoms we perceive as friends, family members or medical personnel:

While numerous aspects of Alzheimer’s have been researched and described, a treatment or cure is yet to be found. Nevertheless, this research has led to some interesting findings…

Connection to Type 2 Diabetes (T2D) 

Did you know that Type 2 Diabetes doubles the risk of dementia? As we hopefully all do know, insulin plays an incredibly important role in diabetes as it regulates blood sugars. However, insulin is multifaceted because it has many other functions as well. For example, in the central nervous system (CNS, your brain and spinal cord), insulin also:

• Influences the growth and survival of neurons,
• Has neuroprotective roles,
• Modulates synaptic plasticity,
• And regulates different receptors (i.e. GABA- and AMPA-receptors)… 

… among other functions.

These demonstrate that insulin is not only important in the body, but in the brain as well. One of the connections researchers have found between Alzheimer’s and diabetes is that a resistance to insulin exists, which oftentimes is initiated by inflammation in the brain (for AD) or in adipose tissue (for T2D). The amyloid beta oligomers (ABO’s or AB plaques, as mentioned in the video above) could possibly be the cause for secretion of proinflammatory cytokines, leading to said inflammation. These ABO’s could also be a cause for peripheral (not in the CNS) metabolic deregulation, which potentially provides a mechanism for why AD patients often also develop T2D. 

Further connections come from the fact that PTP1B can potentiate the inflammation in both diseases, deregulated mTOR signaling contributes to insulin resistance, and abnormal ganglioside metabolism impairs insulin receptor function. 

For more details linking AD and T2D click here.

Did you know that about 50% of all US adults will experience a traumatic event at some point in their lives? I did not. And while this number is higher than I would have expected, luckily most people do not actually develop post-traumatic stress disorder (PTSD) from their experience(s). But why not? What makes one person more likely to develop PTSD than another?

To answer this question, I will first provide a brief background on the disorder.

As mentioned above, the people who do develop PTSD have experienced some form of traumatic event. While that exact event differs from person to person, there are certain types of events that tend to be the source of trauma more often among one sex compared to another. Among women, experiences more likely to be causing PTSD are… 

• sexual assault, and
• childhood sexual abuse

… whereas men’s trauma will probably originate from:

• an accident, 
• physical assault, 
• combat, 
• a disaster or 
• witnessing death/ injury. 

This demonstrates the wide variety of events that can cause this disorder, which 7-8% of the US population (10% of women, 4% of men) suffer from at some point in their lives.

Symptoms

To diagnose PTSD, a person must exhibit numerous of a long list of possible symptoms. These can include persistent and frightening thoughts, flashbacks to the event, becoming startled more easily, sleep problems, detachment, numbness, etc. They also tend to avoid places, people and objects reminding them of the traumatic event. All the aforementioned symptoms, and others, can be grouped into four categories: intrusive memories, avoidance, negative changes in thinking and mood, and changes in physical and emotional reactions.

These symptoms are strongly linked to various brain regions…

The Hippocampus and Amygdala

In people suffering from PTSD, triggering stimuli can induce processes in the brain, leading to the symptoms of PTSD. One of these processes is hyperactivity in the amygdala, which is important for emotion processing and fear responses. These stimuli can include sounds, words, narratives, visual cues, etc. that resemble the person’s traumatic experience, but in some cases the hyperactivity is increased to such an extent that even unrelated stimuli can initiate symptoms.

Due to the importance of memories in PTSD, the involvement of the hippocampus is vital as well. This is a brain region critical for various memory functions, including encoding and retrieval, but in PTSD its volume is significantly reduced. This furthermore makes it difficult for people to discriminate between past and present events. In healthy humans, the hippocampus is supposed to facilitate input into the amygdala, so behavioral responses to the environment are appropriate. However, with a hypoactive hippocampus the amygdala is more likely to go into a state of distress. 

Risk Factors

Now let’s return to our question: Why are some people more likely to develop PTSD than others? The short answer is that there is no single definitive response because science has not yet figured it out (PTSD is very complex). However, a number of theories do exist. For example, two prevalent risk factors for the development of the disorder are previous traumatic experiences and a generally increased level of anxiety. 

The underlying science starts with glucocorticoids and NMDA receptors. When glutamate activates NMDA receptors, MEK is phosphorylated (a phosphate is added) and thereafter ERK1/2 is phosphorylated as well. Glucocorticoids, necessary for the acquisition and consolidation of stressful memories, then go on to interact with the phosphorylated ERK1/2, which in return phosphorylates MSK1 and Elk-1. This allows the chromatin to be opened by H3S10p-K14ac and for gene transcription to occur, specifically genes c-fos and egr1. This gene transcription is critical for memory consolidation, and possibly occurred at an enhanced level in PTSD patients.

Glutamate receptor antagonists strongly inhibit the increase in dual histone mark H3S10p-K14ac, usually thought to occur after stressful events. This may be an option to moderate a traumatic event’s strong impact.

Treatments

The main types of treatment for PTSD include a number of different psychotherapies or medications, which you can read about here.

More recently, research is also looking into the process of Deep Brain Stimulation (DBS) as a treatment option, especially for cases resistant to currently known treatments. The video below provides a description and specific case.

Post- traumatic stress disorder (PTSD) is a mental illness that begins with a traumatic experience and the inability to cope with the experience. This leads to changes in behavior such as negative thoughts or feelings, avoidance, aggression, and being easily startled. Often individuals with PTSD have intrusive memories of the events that manifest themselves as nightmares, flashbacks, or extreme reactions to certain stimuli.

Little is known about what differentiates an individual who will develop PTSD from one who will not under similar circumstances. An area of research that is being explored is stress response and how memories are made based on the stressor.

The region of the brain associated with stress response is the hippocampus which also is influential in consolidating memories. The function of memory consolidation is heightened by glucocorticoids which are stress-induced hormones. Therefore, glucocorticoids are required for consolidation of memories with a stressor. To understand the pathway of how these memories are coupled with the stressor, researchers did a series of experiments, the results or summaries of which are below.

1. Forced swim test: rats placed in a Morris water maze desperately struggle for a time and then become immobile to preserve energy. When placed in maze at a later date, rats become immobile much more quickly. This is an adaptive response.
2. Pharmacological testing: Glucocorticoid receptors in the brain were inhibited to determine which specific receptor leads to the adaptive response. Certain areas of the brain were targeted with the inhibitor to determine which region was responsible for the consolidation of memories for the adaptive response. The glucocorticoid receptors in the dentate gyrus (region of hippocampus) did not elicit the adaptive response of quickly immobilizing when inhibited. Therefore, glucocorticoid receptors in the dentate gyrus are involved in stress response.

3. Dual Histone: an altered histone (protein that wraps up DNA) was found to be in high quantities in the dentate gyrus neurons. These histones increase the expression of the genes, c-Fos (long term changes in brain for adaptive behaviors) and Egr-1 (important for memory formation and learning). The pathway from glucocorticoid receptors to the marked histone was discovered as well.
4. Role of GABA: GABA modulates the effects of stress by reducing anxiety. Exercise increases GABA which reduces the stress response in rats.
5. SMA and the Amygdala: The supra-mammillary area (SMA) stimulates the dentate gyrus via glutamate which is an excitatory neurotransmitter and may add to stress response by inhibiting GABAergic neurons. Processes in the amygdala affect the expression of c-Fos and Egr-1, though the connection isn’t completely understood. In summary, the SMA and amygdala are important in connecting the emotion of anxiety with the environmental information that comes through the dentate gyrus.

What do these findings mean for PTSD? Currently there are no pharmaceuticals that specifically treat PTSD. The primary treatments are different types of psychotherapy with medications commonly prescribed for anxiety. Researching the biochemical pathways of the stress response and strong memory formation processes could eventually advance the treatment of PTSD specifically. However, there is still much research to be done as the mechanism these pathways are incredibly complex and interconnected making it difficult to study. The intricate details must be worked out for each pathway individually but also in the context of the system as a whole.

Type 2 diabetes has been a growing health concern in the United States for a while now and often is caused by diet and lifestyle choices. This disease is marked by insulin resistance. You may be wondering what is insulin and what does it actually do? Well, insulin is a hormone that tells cells to take in the glucose, a sugar, from the blood and use it for energy to run other cellular processes. When the receptors on the cell membrane are resistant to insulin, the blood sugar stays high and causes the other symptoms that accompany diabetes.

Recently, researchers have found that type 2 diabetes patients also have double the risk of developing Alzheimer’s disease. They are related! How can that be? Alzheimer’s disease is a form of dementia and has nothing to do with metabolism. Actually, the connection stems from insulin signaling. Insulin in the brain acts to protect neurons and help the growth and survival of neurons along with glucose metabolism. Insulin is also important in learning because it is a regulator for GABA and AMPA receptors which are important in synaptic signaling. In Alzheimer’s disease, insulin resistance leaves neurons vulnerable.

Understanding that insulin resistance plays a part in both diseases is significant but, insulin signaling is incredibly complex in its functions. This makes it difficult to knowing what is actually leading to the impairment. Some of the mechanisms that are involved in insulin resistance are inflammation, ganglioside activity (sugars anchored in the cell membrane by lipids), regulation of mTOR signaling (pathway instrumental in cell growth and survival), and PTP1B regulation (moderates insulin signaling).

• Inflammation in both type 2 diabetes and Alzheimer’s disease is mediated by a cytokine, small protein that functions in cellular communication, called TNF-α. This particular cytokine induces inflammation and insulin resistance because it usually acts in the immune system.
• Gangliosides disrupt the insulin receptor which acts to prevent insulin from binding increasing insulin resistance.
• mTOR at increased levels leads to insulin resistance by uncoupling IR-1 and 2 which are proteins that trigger the beginning of the insulin signaling pathway in the cell. This shuts the pathway off, preventing insulin from causing a response in the cell.
• PTP1B, a protein tyrosine phosphatase, deregulates the insulin signaling pathway by deactivating IR-1 and 2. PTP1B also down regulates leptin and BDNF signaling which are important for synaptic plasticity.

Another connection to insulin resistance and the two diseases is the buildup of amyloid. In type 2 diabetes islet amyloid polypeptides (IAPP), which function as regulators for insulin and glucagon release, aggregate in the islets of Langerhans (area of pancreas that produces hormones). In Alzheimer’s, amyloid beta subunits of amyloid precursor protein aggregate into Aβ oligomers (ABO) that form Aβ plaques.

In the brain, Aβ’s cause GM3 to build up in the cell membrane which inhibits the insulin receptor. Aβ’s also act in the mTOR pathway and in inflammation, both decreasing insulin signaling.

So, why is the link between type 2 diabetes and Alzheimer’s important? The answer is treatment. Some of the diabetes treatments have shown positive results in Alzheimer’s and suggest that the mechanisms involved in these pathways may be key for future treatment.

The Neurochemistry students are back, writing about all sorts of interesting data and social issues that come with the discussion of the brain!

Enjoy reading….

I cannot thank Concordia enough for the opportunities it has provided me during my four years of enrollment. Not everybody has the privilege of obtaining a liberal arts degree that promotes interdependence and exploration of other fields. While other courses have been a major influence in my growth and development in college, neurochemistry has given me a chance to implement all that I have learned thus far. As my capstone experience, the class was structured to give students an opportunity to become responsibly engaged in the world (BREW) while still receiving support from Concordia’s faculty and services.

The class required the planning, implementation, and analysis of a community action project focused on Autism in our society. We first had to figure out the needs of our community and what type of project could aid in the public’s knowledge, understanding, and acceptance of the disorder. In a group of nine students, we researched and collaborated what options would be most beneficial to the Fargo Moorhead area. We finally decided to hold an interactive workshop for the education majors at Concordia College since they will become the next generation educators who interact with autistic students on a daily basis. After reaching out to many experts, we focused our project content on three simple aspects that can be overlooked by teachers in their classrooms. The first main point we discussed was how to appropriately start a parent-teacher relationship without being condescending or accusing. The next was to emphasize the importance of early intervention and screening for all children because it only can benefit the development of our students and future children. Lastly, we made sure to incorporate some teaching strategies and techniques that are beneficial for all students, but extremely crucial for those with autism.

Our project went exceptionally well and we had great feedback from those who attended. However, the project did not come without a lot of hard work, intensive communication, especially between our nine-membered group, and many challenges. The entire project was aimed towards education majors at Concordia and we only had 3 or 4 show up to our event with the majority being students from other majors. Again I think this information is really beneficial to anyone but extremely necessary for those going into teaching jobs in the near future. Another challenge we faced was contacting people outside of Concordia to possibly talk at our event. It was a major learning experience to understand how hard it is to organize events and coordinate public functions. Even if you have the most valuable information in the world, if you can’t organize efficiently, advertise thoroughly, and effectively present your information, then none of it matters.

It was also beneficial for us to work with another discipline, like social work, to complete this project. It taught us how to be professional but assertive during group meetings and also expanded our field of view about the topic. The neuroscience majors were able to bring in the science behind Autism while the social work students were able to talk about family life, school system, and other aspects of the disorder to give our audience a holistic understanding of the disorder. Also as future doctors, dentists, and scientists, this was a crucial opportunity for us to practice talking to the general public about complicated issues. In our near futures, we are going to be expected to explain diagnosis, procedures, treatments, and medicine to any individual. Another valuable outcome of this project was the realization of my own personal biases and perceptions I had about Autism. Before talking to people personally affected by Autism, I had no idea how much of a financial and emotional toll it has on a family. Lastly, this class as a whole has fueled my love for lifelong learning. Without as many assignments or deadlines, it gave us the freedom to explore the topics as we pleased. Some people would take advantage of this freedom and put in minimal effort, but I feel like our class did a great job of wanting to deep deeper and learn more for our own personal benefit. It was such a fun atmosphere that not only pushed me as a student but as an active member of my community.