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BCL9 and Beta-Catenin’s Functioning in Schizophrenia

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Artstract by Dhruvika Patel

What is Schizophrenia?

Before looking at pathway dysfunction, it’s important to understand what exactly schizophrenia is and its implications. Schizophrenia is a mental condition that can be triggered from not one specific pinpoint of dysregulation, but rather a variety of different genetical, psychological, and environmental factors. This makes preventative measures difficult to take. While it affects less than one percent of the U.S. population, the effects are far from easy to live with. But what exactly does having schizophrenia imply? It normally involves delusions, hallucinations, disorganized speech, grossly disorganized behavior, and withdrawal from social activities. Two or more of these should be seen for a significant amount of time and cannot be due to substance abuse to diagnose an individual with schizophrenia.

Schizophrenia is typically diagnosed in people in their late teens to early thirties, so it is not a condition that necessarily comes with old age. Males are more likely to be

The blue bars represent men vs the red bars representing women for when they are diagnosed with Schizophrenia. More men are diagnosed earlier than women. (1)

diagnosed earlier in their lives than females are; however, this is a condition that is often difficult to recognize in the early phases. To recognize it earlier, symptoms to look for with thinking may be problems with reasoning, bizarre ideas or speech, or confusing dreams or television for reality. Early behavioral problems could include withdrawal from family and friends, trouble sleeping, lack of motivation, not meeting daily expectations, or violent or aggressive behaviors. Emotionally, they would be irritable or depressed, have a lack of emotion, have strange anxieties and fears, or just be very suspicious of others. The range of earlier symptoms could be difficult to tie directly to schizophrenia and not anything else, but as they age, more typical signs and symptoms (ie. delusions, etc.) will appear.

Wnt Signaling and Schizophrenia

Patients with schizophrenia have a lower cognitive ability which may be a result of wnt signaling pathway development or rather lack of. The beta-catenin functioning properly in the wnt-signaling pathway is vital in synaptic plasticity of the neurons in human brains. Normally, GSK will be inhibited in the wnt-signaling pathway, which will allow beta-catenin to get to the nucleus. If GSK is not inhibited, it will tag the beta-catenin to go to the proteosome instead to be destroyed. Beta-catenin’s interactions in the nucleus is important for cell proliferation, differentiation, and apoptosis. Beta-catenin is important for the transduction of the signal to the nucleus and once it reaches the nucleus, it can transcribe the wnt-related genes that control cell fate in cells and tissues.

BCL9 and Beta-Catenin’s success

BCL9, B-cell lymphoma 9, is often not emphasized in the wnt pathway, but it does have an important role in Beta-catenin’s proper functioning. What is BCL9 and where does it come from? B-cell lymphoma is a large protein encoded by the BCL9 gene expressed in all tissues of the body. In the wnt-pathway it works with another protein, PYGO, to tether Beta-catenin to TCF/LEF. This tethering allows for efficient T-cell factor mediated transcription in the wnt signaling pathway; without it, the beta-catenin may not properly bind to the transcription factors to transcribe the necessary genes. Think of BCL9 acting like cupid to bring the transcription factors and beta-catenin together.

(2)

Conclusion

Schizophrenia is not necessarily an easy condition to diagnose until the symptoms become more obvious. It makes one wonder possibilities for what may be causing this. One pathway that alterations can cause problems with is the wnt pathway. The wnt signaling pathway is composed of such a variety of components that affect its proper functioning. The final goal is for beta-catenin to transcribe the appropriate genes, and dysfunction here can lead to a multitude of mental disorders including Schizophrenia. One of the many important components of the success of this pathway includes BCL9, with its function vital in tethering the beta-catenin to the transcription factors.

Citations:

  1. https://www.nature.com/articles/s41537-020-0102-z
  2. https://www.nature.com/articles/s41375-019-0404-1

 

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Gaining Empathy for the Mentally Ill: Schizophrenia Edition

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Schizophrenia is a debilitating disease that effects 24 million people worldwide, 2.8 million of those people being in the United States. Schizophrenia is a disease that affects how a person, thinks, feels, and behaves. There are people, just like you and me, that are struggling with hallucinations, delusions, disorientated thinking, and impaired daily function.

When diagnosing schizophrenia, there are two sets of symptoms that are quite distinguishable. A psychologist will be looking for positive and negative symptoms. Positive symptoms include hallucinations, delusions, and disorganized speech. Negative symptoms include flattened affect, reduced speech, and lack of initiative.

It has been proposed that schizophrenia might develop sooner than we have previously seen. Most people get diagnosed in adolescence, but it is hypothesized that abnormalities could begin in utero along with early environmental influences such as infection.

Changes in the Brain: Physical and Molecular

There are many changes that can be seen in the brain when looking at people diagnosed with schizophrenia. Smaller total volumes of brain tissue and less gray matter. Schizophrenia affects many adolescents and young adults, so the image to the right shows the rate of gray matter loss in schizophrenic adolescents. It can be seen that there is a faster rate of loss within the parietal (top) and temporal (side) parts of the brain.

Those are some physical changes in the brain that can be seen by imaging. There are molecular changes that are happening in the brain that can’t totally be seen. Schizophrenia can be linked to the Wnt pathway, which with more research, can help lead to better treatments.

Overactive dopamine is binding to its receptors (D2) which inhibits the Akt enzyme. The inhibition of this enzyme will in turn decrease the inhibitory phosphorylation of GSK3-beta. If GSK3-beta is not inhibited, it will remain a destruction complex in the Wnt pathway. With this complex still in place, beta-catenin will continue to break down and gene transcription does not happen. Without gene transcription, genes important for neural development will not be expressed. When these genes are not expressed, abnormal functioning and development occurs which can ultimately lead to schizophrenia.

Schizophrenia is a complex disease that is very difficult to study and research. It is hard to model schizophrenia in a lab which is why the treatment options and research is so slow. Finding out the that Wnt pathway is involved in schizophrenia is a big advancement in the etiology and treatment of this disease. With new genetic findings and animal and human stem cell models, there will be the ability to gain a deeper understanding of all neuropsychotic disorders not just schizophrenia.

How to Gain Empathy for the Mentally Ill

Mental illness can change the course of someone’s entire life. Even with treatment, their life will be filled with psychiatrist appoints, therapy sessions, pharmacy visits, and people treating them differently. The negative stigma around mental illnesses has gotten better over the years, but there is always room for change and improvement.

People with mental illnesses cannot help it. It is not their fault, and it never will be. They can barely get the help that they need so we do not need to add to the stress. I think that education and advocation is something every person should care more about when it comes to the mentally ill. Taking the time to research a mental illness or asking respectful questions or standing up for people with mental illness when they are not able to stand up for themselves is essential.

There are many TV shows, movies, and books that depict the life of those with mental illnesses. While these can bring awareness to living with mental illnesses it is important to remember that these are more than likely dramatized and do not show accurate depictions of what it is really like to live with these types of illnesses.

One of the best books that I have read that accurately shows schizophrenia and what it is like is the book called Challenger Deep by Neal Shusterman. This book follows a young boy who has schizophrenia and his daily struggles. We get a glimpse into the mind of someone with schizophrenia and this sort of thing hasn’t been done too often.

 

 

References:

Jodi Clarke, M. A. (2022, May 20). Signs and symptoms of schizophrenia. Verywell Mind. Retrieved February 19, 2023, from https://www.verywellmind.com/what-are-the-symptoms-of-schizophrenia-2953120

NEALSHUSTERMAN. (2020). Challenger deep. Amazon. Retrieved February 19, 2023, from https://www.amazon.com/Challenger-Deep-Neal-Shusterman/dp/0061134147/ref=sr_1_1?crid=1H3WVMZLS747J&keywords=challenger%2Bdeep&qid=1676832807&sprefix=challenger%2Bdeep%2Caps%2C185&sr=8-1

Singh, K. K. (2013). An emerging role for Wnt and GSK3 signaling pathways in Schizophrenia. Clinical Genetics, 83(6), 511–517. https://doi.org/10.1111/cge.12111

Wnt signaling*. WormBook Header Image. (n.d.). Retrieved February 19, 2023, from http://www.wormbook.org/chapters/www_wntsignaling/wntsignaling.html

 

Disease/Health

Amyloid Beta Plaques, Insulin Resistance, and Alzheimer’s Disease

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Introduction

Alzheimer’s Disease (AD) is a neurodegenerative disease classified by cognitive impairments of memory loss, critical thinking, and social skills. Recently, research has begun connecting the lack of insulin to the progression of Alzheimer’s. Insulin is connected to improved cognitive function and memory. However, decreased insulin has previously been observed as being a defect of the pancreas and playing a role in type 2 Diabetes Mellitus.

Insulin in the brain

Insulin enters the brain either peripheral or is produced directly in the brain. Insulin produced peripherally must cross the blood brain barrier (BBB) through a transport system to act within the brain. Once in the brain insulin binds to insulin receptors (IR) which are primarily located within the hippocampus and the cortex. The binding of insulin to IRs results in the regulation of metabolism, cell differentiation, survival, and growth. However, in the presence of insulin resistance Alzheimer’s Disease begins progressing.

Insulin resistance and Alzheimer’s

The amyloid beta protein is naturally produced within the brain and is responsible for assisting in nerve growth and repair. However, improper cleaving by the secretase enzyme results in a misfolded beta sheet secondary structure protein that binds to other misfolded proteins. The oligomer that forms from the misfolded protein binding is an amyloid beta plaque. Amyloid beta plaques bind to IRs therefore, competing with insulin to bind to the IR. Increased binding of plaques result in the formation of more plaques and lessen the presence of insulin and the amount of insulin binding to IRs in the brain. Additionally, the binding of amyloid-beta plaques to the insulin receptors causes signaling dysfunction of the PI3K pathway which in turn activates the GSK-3ß pathway. The dephosphorylation of GSK-3ß pathway leads to the phosphorylation of Tau proteins. Tau proteins make up the microtubules found in neurofibrillary tangles (NFTs). The formation of NFTs block synaptic communication and eventually lead to neuronal death. The presence of plaques, NFTs, and neuronal death are the major characteristics of Alzheimer’s Disease.

Conclusion

A major risk factor of amyloid beta plaque formation is based off of diet. A diet consisting of high omega-3 fats, reduced sugar, whole grains, fruits, and vegetables while avoiding processed foods are shown to reduce the potential of amyloid beta plaque formation and buildup. However, if Alzheimer’s has already set in neuronal death cannot be reversed but it could be slowed or stopped. No definite treatments exist to stop the spread of AD, but promising results have been observed with exenatide-4 treatment. Exenatide-4 targets and activates the PI3K and Akt pathways which phosphorylates and deactivates the GSK-3ß pathway. Deactivation of the GSK-3ß pathway will decrease tau phosphorylation, directly limiting NFT formation and slowing neuronal death and the affects of Alzheimer’s.

Exenatide-4 structure

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Diabetes and Cognitive Decline

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Insulin

Insulin is a peptide hormone with numerous functions in the body, the most common of which is to control glucose levels. Insulin acts differently in the pancreas, liver, bones, and so on than it does in the brain. Insulin regulates neuron growth, survival, differentiation, and communication in the brain. So, what happens when insulin is not properly regulated?

Insulin resistance

This is a condition in which the body and brain are unable to use glucose as an energy source effectively. The ability to be insulin sensitive is lost, and as a result, glucose absorption by brain cells is compromised. Insulin regulates brain metabolism and overworked insulin receptors cause brain cells to die. Chronic oversupply of glucose to brain cells causes the cells to overwork in order to metabolize the excess fuel, eventually giving up and committing suicide via a process known as apoptosis.  

This has an effect on neuro communication in the brain because glucose is what the cells require to function properly. At this point, the brain is essentially starving. There is an abundance of glucose but no way to use it. 

 High carb content diets, like the typical American diet promote chronic and prolonged blood sugar spikes. This prolonged glucose overdose starves the brain and later  manifests itself as cognitive impairment. Cognitive ability is directly proportional to energy supply to the brain.

Diabetes

It is critical to distinguish between type I and type ii diabetes. We lack the ability to produce insulin in type I diabetes, so glucose levels in our bodies are high. In type II diabetes, however, insulin is present, but it is excessive, and our cells become resistant to it, raising glucose levels to dangerously high levels. When we think of diabetes, we usually think of the heart, kidneys, and pancreas as the most affected organs. But what about the brain? 

Diabetes accelerates brain aging, which, as we know, causes neurodegenerative diseases such as Alzheimer’s. Blood flow to the brain is reduced in diabetic patients, causing neuron damage. These neurodegenerative changes occur at a much earlier stage. Diabetes also impairs byproduct metabolism in patients, resulting in the buildup of undesirable substances such as amyloid plaques and neurofibrillary tangles found in Alzheimer’s disease.

In diabetes, people have smaller brain volume of the frontal and temporal lobes due to brain atrophy triggered by excessive cell apoptosis.

Inflammation and Alzheimer’s Disease

When most people hear the words Alzheimer’s disease, they envision plaques and tangles. We know that amyloid plaques and neurofibrillary tangles are major indicators of neurodegenerative disease, most notably Alzheimer’s disease.

Plaques cause one of three problems in the brain:

  • Disruption of neuron communication by acting a physical barriers in synapses
  • Trigger inflammation through the intervention of the immune system
  • Increased risk of hemorrhage in blood vessels through amyloid angiopathy

Tangles form when plaques accumulate outside of neurons. Tangles cause significant disruption in the cell’s transport system, the microtubules.

Tangles, combined with plaque buildup, eventually cause the cells to die via apoptosis. This explains why reduced brain atrophy, a condition caused by too much cell death in the brain, is a major symptom of Alzheimer’s disease.

If this blog is to be of any use to you, I want you to be able to link insulin to the formation of plaques and tangles, and, in the larger picture, Alzheimer’s disease.

 

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Insulin in the Brain?

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When you hear insulin typically you think of blood sugar, the pancreas, or diabetes. Did you know it is in your brain as well? Well, if you didn’t no worries, until recently the brain was classified as an organ without it or just insensitive to insulin. Before we get into the logistics. Let’s review what insulin is exactly.

Insulin, when created in the pancreas is a hormone the allows glucose (aka sugar) to enter your blood stream. While in the brain it actually functions as a neuromodulator that helps neurons exist. According to a review, it is involved in neuronal survival, energy production, gene expression, and synaptic plasticity. As well as the breakdown of glucose as well. Metabolism or breakdown of glucose in the brain has been linked to have effect on how your neurons are able to learn and a persons’ memory.

A study has also showed that in mice neurons contain mRNA of preproinsulin. Which is insulin but in its’ “pre-hormone state”. It was found in all parts of the neuron including synapses. This leads to the synthesis of insulin. Insulin can also enter the brain from systems outside of the CNS. It enters through the BBB (blood brain barrier) by beta pancreatic cells.

So how does all this pertain to Alzheimer’s disease? (AD) Well, the by mistakes in the insulin pathways in the brain. Or a more common term, insulin resistance. Insulin receptors which control the breakdown of glucose in the brain. In turn can regulate of the overall health of neurons. Well, if the transmission of insulin gets wonky or in scientifical terms things like beta amyloid competition. Insulin cannot bind as well, which can lead to neuronal death. Therefore, insulin resistance can increase the pathology of AD.

Not only does insulin play a role in cognitive functions. Studies have also shown that it plays a role in anxiety and depression in the brain. Neuronal-specific insulin receptor knockout (NIRKO) has shown to increase anxiety and depression like symptoms in mice. Research has also shown that insulin can alter body weight and appetite. It can both increase and decrease appetite, which one? Well, it depends on how the insulin got to the brain.  Shockingly it increases appetite when insulin enters the brain peripherally. Synthesized insulin or the insulin made in the brain is what can cause a decrease in appetite and lowers body weight. Below is a little figure that I find helpful to keep track of how insulin plays a role in all parts of our bodies. And how in each part in changes different things for us.

Being that research about insulin in the brain is all new, the possibilities of new findings can lead to remarkable actions we may be able to take to monitor our own health. Insulin in the brain has already been linked to having effects memory, neurological diseases, mental health, and our physical health like appetite and weight. Who knows maybe one day insulin will be something everyone will be familiar with, not just those who have to monitor blood sugar levels. It will be something everyone will want to monitor for themselves to live a long and better quality life.

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Alzheimer’s disease and the need for healthier lifestyles

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Alzheimer’s disease and broader dementia are a growing epidemic challenging care for global ageing populations. Characterised as a neurodegenerative disease, Alzheimers involves the degeneration of the brain and a subsequent loss of cognitive function. Memory loss, confusion, and delusion all plague patients with Alzeihmers, and so too, the family and caregivers who care for these individuals. As this disease becomes more prevalent amongst our future ageing population, intriguing research is coming forward on the causes of Alzheimer’s and even some of the ways to prevent it. A review by Ansab Akhtar and Sangeeta Pilkhwal Saw out of Punjab University in Chandigarh, India is presenting some useful insight on the effects of insulin to the brain. 

In order to understand this, however, we must first assess the two largest factors that contribute to the neurodegeneration in Alzheimer’s disease. The first is amyloid-ꞵ plaques. ꞵ-amyloid is a small protein that can misfold and connect with other ꞵ-amyloids to form a plaque-like formation outside of a cell. When this plaque forms, it inhibits the binding of insulin to its receptors in the brain. The second contributor to Alzeimhers important in understanding the effects of insulin are neurofibrillary tangles or NFTs. NFTs arise when Tau proteins become hyperphosphorylated leading to tangle formation in microtubule networks which leads to their collapse. In other words, look at Tau protein as a Jenga block at the very bottom of a tower that resembles the framework of a cell, otherwise known as microtubules. When this block is removed, the microtubule tower falls and so does the cell that it provided a framework for. NFTs are much like the fall of a Jenga tower. 

Insulin is crucial to the action of both amyloid-ꞵ and NFTs. Insulin is responsible for regulating blood sugar throughout the body but it plays a valuable role in protecting the neurons in the brain. The review by Akhtar and Saw provides insight into how the brain developing resistance to insulin is related to the formation of amyloid-ꞵ plaques and NFTs. The first figure placed in the review shows the various ways the insulin signalling pathway can be affected. Many of the molecules inside the cell can contribute to NFT formation internally whilst also allowing amyloid-ꞵ to be produced which can stop insulin signalling all together at its receptor. When there is dysfunction of this insulin pathway, the neurons do not function optimally and often undergo apoptosis, which is programmed cell death. 

Understanding insulin resistance is valuable in understanding Alzheimers and treating it in our future. Processed food products are used by societies across the globe to ensure cheap and abundant food. This abundance, however, has led to metabolic syndrome and an increase in insulin resistant diabetes in our communities. Being one of the largest contributors to these problems, changing our diets should be a starting point. Whole, unprocessed foods take more metabolic effort to digest and minimise the blood sugar spikes we see from processed counterparts. Much like how they slow down digestion, these whole foods also slow down our day to day lives. Taking more time to focus on our diet also allows us to make greater effort towards our physical activity. A healthier society may see less insulin resistance which may be one of the first steps we can make to stopping Alzheimer’s disease in its tracks. 

 

Ansab Akhtar and Sangeeta Pilkhwal Saw, “Insulin signaling pathway and related molecules: Role in neurodegeneration T and Alzheimer’s disease” Neurochemistry International 135, (2020)


Disease/Health

What is Alzheimer’s Disease?

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Drawings by artist William Utermohlen

What is Alzheimer’s Disease? It is something that so many people hear about, so many people see firsthand, but something that not many people know much about. I will refer to Alzheimer’s Disease as “AD.” AD is a neurodegenerative disease that destroys memories that are important for memory functioning. More specifically, cells in the brain deteriorate and eventually die off. This is something that cannot be reversed but could potentially be avoided, and symptoms of AD could be lessened through medications, as well as lifestyle changes.

Scientists have begun to refer to AD as Type 3 Diabetes (T3D). The two types of diabetes that come before T3D are caused by a complete loss, or partial loss, of a hormone in the body called insulin. Insulin regulates levels of sugar in the blood, and when those levels get too high it leads to complications in the body. One of these many complications is diabetes. Another complication, not directly related to blood sugar levels but related to insulin, is AD. AD can be caused by genetics, but it may also arise from certain lifestyle decisions. For example, an unhealthy diet, high blood pressure, high cholesterol, and a diagnosis of T1D or T2D can lead to a future diagnosis of AD. All these lifestyle decisions can lead to insulin resistance. This concept means that the body’s cells don’t respond to insulin like they normally should.

Insulin is produced by cells in the brain, called neurons. Insulin can also be transported into the brain through the blood brain barrier (BBB). The BBB is made up of blood vessels and tissues that are closely connected by cells that keep out harmful substances out of the brain and keep other substances from leaking out of the brain. There are different signaling pathways that are important for normal insulin functioning in the brain, but one of the most prominent signaling pathways is the PI3K/Akt pathway. When a person becomes diagnosed with AD, it has been concluded that insulin sensitivity is reduced and the PI3K/Akt pathway is dysregulated. When this pathway is activated, it is responsible for glucose uptake as well as metabolism. When the PI3K/Akt pathway is dysregulated/less activated, there are much higher levels of glycogen synthase kinase-3 beta (GSK-3β). This enzyme is responsible of the regulation of the metabolism of glycogen. This process plays a major role in inflammation and cell production. Enhanced activation of the GSK-3β is responsible for phosphorylation, the addition of a phosphate onto a molecule or ion, of the tau protein in the brain. The tau protein helps stabilize the internal skeleton of neurons in the brain, it takes the shape of a tube, allowing for the support of the internal skeleton. When the tau protein is phosphorylated, neurofibrillary tangles can form. If a tau protein becomes phosphorylated too much, it will no longer support the neurons and multiple tau proteins will join and form tangles. These tangles lead to blockage of the neuron’s transport system, meaning that neurons no longer communicate efficiently.

Overall, many things can contribute to a person’s diagnosis of AD. Underlying conditions, bad diet, genetics, and insulin resistance. A few medications have been shown to help with AD, especially some diabetic medications. However, there is no medication or therapy that will reverse this disease. There are changes in one’s life that can help avoid AD, however it is a neurodegenerative disease that has major consequences.

Health

Neurofibrillary Tangles and Insulin Resistance in Alzheimer’s Disease

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Artstract by Jessica Howard

Artstract by Jessica Howard

Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurological disease marked by a degradation of neurons and loss of brain tissue. It is most common in the elderly and is marked by loss of cognitive function. The symptoms include decline in memory formation and retrieval, and social skills. There is also usually a deviation from normal behaviors for that individual. As the disease progresses a person’s ability to perform daily activities and independence is eventually loss. The two pathological markers of AD are amyloid-B plaques and neurofibrillary tangles.

Insulin Resistance and Amyloid Plaques

Amyloid-B plaques are misfolded protein waste that are difficult for the brain to break down, these plaques can then build up in the space between nerve cells. Insulin resistance is a term to describe when insulin in the brain is unable to perform at optimal functioning. Amyloid plaques are one of the contributors to insulin resistance by acting as competitors for insulin signaling to its receptors in neurons. This results in disruption of several functions inside the neuron that would normally be controlled by insulin signaling.

Insulin Resistance and Neurofibrillary Tangles

Neurofibrillary tangles (NFTs) are a buildup of a deactivated protein called the tau protein. This protein is used as structural support for microtubules, which are like small tunnels used to transport nutrients, inside the neurons. When insulin resistance is present in the cell it leads to the activation of a kinase, which is used to start chemical reactions. This kinase in particular is responsible for the deactivation of the tau protein. Therefore, when the tau protein is deactivated, it removes itself from the microtubules, tunnels, and the tau proteins get tangled up with each other. Think of it like friends going off to hold hands. Now there is nothing holding the tunnels up, so they collapse. Remember these tunnels are used for transportation so their absence makes it very difficult for the neuron to go about its daily tasks. Eventually, too many of the tau proteins leave their posts to go hold hands and the cell dies because it can no longer function. After the cell dies the neurofibrillary tangles are left behind in the shape of the cell that they inhabited, these are called ghost cells.

Decreasing Risk for Alzheimer’s Disease

There are currently no ways to remove amyloid plaques or NFTs from the brain. But there are ways to prevent these formations to stave of AD. One of the most important ways to prevent insulin resistance is to maintain a healthy lifestyle. This includes actions such as getting regular physical activity each week and sticking to a balanced diet. Diet is especially important for individuals with diabetes as this can put them at greater risk for insulin resistance. These may seem like simple actions, but they can go a long way reducing risk for AD later on in life, especially if implemented early and maintained.

References:

Akhtar, A. & Sah, S. P. (2020). Insulin signaling pathway and related molecules: Role in Neurodegeneration and Alzheimer’s disease. Neurochemistry International 135. Doi: https://doi.org/10.1016/j.neuint.2020.104707.

Monoley, C. M, Lowe, V. J., & Murray, M. E. (2021). Visualization of neurofibrillary tangle maturity in Alzheimer’s disease: A clinicopathologic perspective for biomarker research. Arzheimers & Dementia 17(9), 1554-1574. Doi: https://doi.org/10.1002/alz.12321.

https://www.news-medical.net/health/What-are-Amyloid-Plaques.aspx#:~:text=Amyloid%20plaques%20are%20aggregates%20of,memory%20and%20other%20cognitive%20functions.

https://www.brightfocus.org/news/amyloid-plaques-and-neurofibrillary-tangles

https://www.cdc.gov/aging/publications/features/reducing-risk-of-alzheimers-disease/index.htm

Health

Preventing Insulin Resistance in Alzheimer’s Through Diet

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Alzheimer’s disease is a neurodegenerative disease that causes difficultly with cognitive function, behavior, and day-to-day life functioning and it effects over 44 million people today. Although there has been extensive research over the years, there is little clarity when it comes to the cause of Alzheimer’s. In turn, there are no sure-fire ways to treat it or prevent it. But now, studies show the presence brain insulin resistance in those with Alzheimer’s.

Possible Causes of Alzheimer’s

Amyloid beta plaques and neurofibrillary tangles have been known to be the main causes of Alzheimer’s disease. The Alzheimer’s Association notes that amyloid beta plaques and tangles lead to impaired cell signaling and inflammation. This leads to cell death.

Amyloid beta plaques are made up of smaller pieces known as beta-amyloid proteins. Shown in this image, amyloid beta plaques clump between neurons and cause disruption of cell signaling.

Insulin and Alzheimer’s

Insulin plays a role in the brain by altering, regulating, and protecting neurons. Insulin can protect neurons by stopping the amyloid beta plaques from building up. When inflammation is present, insulin resistance occurs. In this case, insulin cannot function properly, and the amount of insulin degrading enzymes decreases. Insulin degrading enzymes also degrades amyloid beta plaques. With decreased insulin degrading enzymes, amyloid beta plaques build up, causing cell death and Alzheimer’s symptoms. ¹

Inflammation

Inflammation can be caused by a poor unbalanced diet. Intake of too many saturated fats can lead to inflammation. While eating unsaturated fats and antioxidants can reduce inflammation and oxidative stress.

Oxidative stress is caused by the presence of too many oxidants and not enough antioxidants. Antioxidants play a role in protecting tissue. But, in Alzheimer’s disease antioxidants are depleted and oxidative stress causes inflammation. ²

Cytokines are proteins to regulate inflammation. Continued inflammation of the brain causes cytokines to continually release. Cytokines will then allow peripheral immune cells to enter the brain creating a continual inflammatory response. Therefore, the presence of these pro-inflammatory cytokines will lead to insulin dysfunction.

Mediterranean Diet and Inflammation

The Mediterranean diet has been proven to have anti-inflammatory effects. As stated previously, eating a diet that consists of unsaturated fats versus saturated fats as well as adding antioxidants helps to reduce inflammation and oxidative stress. The main source of fat comes from olive oil which is an unsaturated fat. This diet is also characterized as being high in antioxidants with a high amount of fruits and vegetables. It has then been shown that those who stick with the Mediterranean diet are less likely to develop Alzheimer’s.

Additionally, a diet with a high intake of pro-inflammatory foods such as red meat, processed meats and fried foods has been shown to lead to cognitive decline. ³

What should we do?

As of right now, there is no way to reverse Alzheimer’s, but we can prevent it. Given the promising effects of the Mediterranean diet, it can be possible to prevent Alzheimer’s through diet. I believe the best course of action would be to catch insulin resistance early. Similar to screening for prediabetes and type 2 diabetes, the same screening could be done in light of preventing Alzheimer’s. Essentially, preventing type 2 diabetes would be preventing Alzheimer’s. Treating type 2 diabetes would also be early intervention of Alzheimer’s by addressing insulin resistance.

  1. Akhtar, A., & Sah, S. P. (2020). Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease. Neurochemistry international, 135, 104707. https://doi.org/10.1016/j.neuint.2020.104707
  2. https://tissuerecovery.com/blogs/brain/improve-your-memory-by-reducing-oxidative-stress
  3. McGrattan, A. M., McGuinness, B., McKinley, M. C., Kee, F., Passmore, P., Woodside, J. V., & McEvoy, C. T. (2019). Diet and Inflammation in Cognitive Ageing and Alzheimer’s Disease. Current nutrition reports, 8(2), 53–65. https://doi.org/10.1007/s13668-019-0271-4
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Inflamed Brain

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Inflamed Brain

medical illustration – swollen, painful brain

Neuroinflammation (inflammation of nervous tissue) is a continuous state of immune system response. In acute (short term) inflammation, cells will release signals in response to injury or infection. These signals will alert immune cells, which will then response and solve the problem. It’s when an acute response goes wrong that inflammation becomes a problem. In chronic inflammation cells will keep release signals and the immune cells can’t fix the problem, causing constant and long-term inflammation. This chronic inflammation is often associated with age and neurodegenerative disorders.

Key Players:

Microglia: the innate immune cells of the CNS. They are constantly patrolling and watching for infection or injury to respond to. They respond rapidly, and are the first and main form of immune defense in the brain. They often recruit other immune cells to aid in their roles. It’s easy to think of them as the cops of the brain.

Cytokines: a family of proteins that regulate many cell processes, including cell development, death, and inflammation. When cells sense a foreign thing or are injured they will secrete pro-inflammatory cytokines as a signal to microglia that there is something wrong. Their role in inflammation is essentially waving a red flag to get microglia’s attention.

Alzheimer’s Disease:

Alzheimer’s is a neurodegenerative disease that is characterized by beta-amyloid plaques and neurofibrillary tangles. Beta-amyloid plaques are build-up of amyloid-beta proteins outside of the cell, and tangles are the build up of a Tau proteins inside of the cell. Both of these protein clumps interfere with neuron communication and eventually lead to neuron death. The plaques and tangles that appear with Alzheimer’s disease are not supposed to be present in the brain. As such, when cells sense these deposits they secrete pro-inflammatory cytokines to alert the immune system that there is something that needs to be fixed. The microglia that are patrolling the brain respond to the build up of these proteins, and are also recruiting other immune cells to help. However, microglia and other immune cells are not able to effectively destroy the beta-amyloid plaques, and since the tangles are present only inside the cell, they aren’t able to do anything about the tangles and the cell will eventually die. But the immune cells don’t give up! They keep attempting to destroy the plaques, and cells will keep releasing pro-inflammatory cytokines. This prolonged response causes the chronic neuroinflammation that is present in Alzheimer’s disease.

Breaking the Brain’s Armor:

As mentioned before, cytokines do a ton of things in the body. They regulate inflammation and also cell survival. The excessive release of cytokines during chronic neuroinflammation can have some damaging effects. You may have heard of the blood-brain-barrier (BBB), the BBB is a layer of cells and blood vessels that surround the brain and protect it from the environment of the rest of the body. It let’s the good things in and keeps the bad things out. Think of it like a set of armor or a shield surrounding the brain. Too many cytokines circulating the brain can damage the BBB, and allow outside cells and proteins into the brain. During neuroinflammation the BBB is often compromised, which allows peripheral (body) immune cells to be recruited into the brain by microglia. These peripheral immune cells increase inflammation and worsen neuroinflammation.

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