Cobbers on the Brain

Linking Alzheimer’s Disease and Type II Diabetes

The Link

When picturing an individual suffering from Alzheimer’s disease (AD) and one suffering from Type II Diabetes (T2D), these pictures look greatly different. However, zooming in past the physical symptoms and appearances, we can look closely at the specific ways these disorders work. Tied together by the mechanisms of neuroinflammation, insulin resistance, and ganglioside function, AD and T2D are more similar than we might imagine.

Image 1: The biological connections in grey can be studied between AD and T2D and represent the two-way street these disorders pave in our brains.

What is Insulin?

Insulin is a hormone generally made in the pancreas that helps our body take in glucose, which is processed and used for energy and stored in our cells for future use. In diabetes, this process does not function. In type II diabetics, insulin is produced but not able to complete the signaling pathway to intake glucose.

The Pathway:

Insulin leads to the uptake of glucose through the pathway represented in the above image. Insulin binds to the transmembrane insulin receptor (IR). This activates the IRS1, leading to a phosphorylation cascade ending with the translocation of GLUT receptors to lipid rafts (compartmentalized sections) in the membrane.

Understanding Alzheimer’s:

Alzheimer’s disease is characterized by the buildup of amyloid plaques and neurofibrillary tangles in the brain. The pathway to these malformations is complex, but has many connections to neuroinflammation and insulin resistance.

Connecting the Pieces

The pathways of AD and T2D connect through insulin resistance and neuroinflammation. The two figures below detail the complex mechanical connections between the diseases. More specific information on these topics can be found at source links 1 and 2 below.

Image 3: Insulin resistance affects the production of glucose peripherally. This dysfunction in the CNS contributes to the formation of amyloid beta plaques and neurofibrillary tangles in the brain.

 

Image 4: This pathway shows that many factors (ex: PKR, S6K, PTP18, GM3) directly inhibit the processing of insulin. The buildup of GM3 molecules physically disassociates the IR from its connection with IRS 1/2, causing reception to be halted. The GD3 molecules that are made from GM3 perpetuate the buildup of Amyloid Beta plaques, showcasing the connection to AD.

So what?

Using the connections in mechanism between T2D and AD can inform future treatment options and research in both conditions. Seeing the parallel nature in pathophysiology between the conditions, it isn’t surprising how often the two disorders overlap. The knowledge gained from a dual-perspective view at both AD and T2D can influence further research in not only these conditions, but also other neurodegenerative conditions involving neuroinflammation due to the buildup of malformed molecules in the brain. This research has the potential to impact a large community of individuals and family members who are affected by neurodegenerative diseases or Type II Diabetes.

Sources for further research

• https://www.researchgate.net/figure/Schematic-diagram-of-the-insulin-signaling-pathway-Binding-of-insulin-to-the-a-subunit_fig2_232231667
• http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1980-57642017000200105
• https://www.abcam.com/pathways/overview-of-insulin-signaling-pathways
• http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1980-57642017000200105
• https://www.google.com/search?biw=1241&bih=715&tbm=isch&sa=1&ei=WRa8W6OxPO-l_QbNw6-ICA&q=alzheimers+and+diabetes&oq=alzheimers+and+diabetes&gs_l=img.3..0i10i24.15202.17476..17593…1.0..0.297.2054.4j5j4……1….1..gws-wiz-img…….0j0i10.cMHLL_jyY7Y#imgrc=67SBnaVcq0xlOM:

The Concordia College Neuroscience Program aims to consider and connect as many interdisciplinary perspectives as possible. As students, we are taught to think critically and connect our experiences to the curriculum. This perspective helps in discussing the possible causes and connections in neurodegenerative diseases. When discussing Alzheimer’s Disease this week, the class considered the similar pathways and concepts we learned last week with Autism Spectrum Disorder (ASD). Students also considered their personal connections and experiences with neurodegenerative diseases.

Although we have all learned about Alzheimer’s Disease in our courses, many of us also have personal connections to the neurodegenerative disease. According to the 2018 facts and figures released by the Alzheimer’s Association, 5.7 million Americans currently live with Alzheimer’s Disease. The number of deaths related to Alzheimer’s Disease has increased by 123% from 2000-2015. The association notes that every 65 seconds, another individual develops Alzheimer’s Disease in the United States. Cases of dementia, including Alzheimer’s Disease, are responsible for the death of 1 in 3 senior Americans–this is more than Breast Cancer or Prostate Cancer combined.

Like a few of the other students in the class, I have a familial connection to Alzheimer’s Disease. Due to many members within the older generation of my family developing Alzheimer’s Disease, I fear that I too may develop the disease in the later years of my life. We know from previous research that there is a hereditary factor linked to Alzheimer’s Disease. Previous research has shown that mutations in genes APP, PSEN1, and PSEN2 have linkages to early onset Alzheimer’s. Likewise, research on late-onset Alzheimer’s Disease found 20 different genetic loci associated with the disease. Specifically, APOE4 is a gene correlated with the familial development of Alzheimer’s Disease–one that shows the heritability of the disease. Regardless of the heritability and genetic factors of dementia, previous research has also shown the importance of the environmental factors associated with the development of the disease–and in many cases, the genetic and environmental factors both contribute to the development of Alzheimer’s Disease. Paying attention to these environmental factors may decrease my chances of developing this neurodegenerative disease.

These environmental factors include:

• Diet
  • Type 2 Diabetes has been linked to Alzheimer’s
  • The insulin resistance leading to Type 2 Diabetes likely stems from a fatty diet
  • Other popular media articles have discussed how red meat might lead to Alzheimer’s
  • The prevalence of Alzheimer’s Disease in the United States more than likely is due to our diet and lack of exercise.
• Exposure to toxic chemicals
• Serious brain injury
• Air pollution

When discussing Alzheimer’s Disease and many other neurodegenerative diseases, it remains important to note the vital interaction between genetic and environmental factors resulting in the development of disease. With the prevalence of genetic testing in today’s society, specifically through companies like 23andMe, people can know in approximately 6-8 weeks if they possess some of the genes associated with Alzheimer’s Disease. Without proper consideration or education, members of society may be mislead to think that they are destined to develop the disease. That may not be the case. It is more likely that even if an individual possesses the gene associated with a disease, environmental factors play a large role in whether or not that gene is transcribed or “turned on.” Research has shown that paying attention to the environmental risk factors above, and changing lifestyles to match, may reduce a person’s risk for Alzheimer’s Disease.

https://moodle.cord.edu/pluginfile.php/723477/mod_resource/content/0/2018%20AD%20and%20insulin%20signaling.pdf

https://www.alz.org/media/HomeOffice/Facts%20and%20Figures/facts-and-figures.pdf

 

In a society that values convenience, it should not come as a shock that 1 in 4 Americans eats fast food every day. Aside from poor eating habits, it has been found that nearly 70% of one’s waking hours are spent being sedentary, and yes that is referring to the copious amount of time you spend on the couch binge watching Netflix. Taking all of these factors into consideration, it is not surprising that nearly 40% of Americans are obese, not simply overweight, but obese. The more weight that an individual has, the greater the risk of their body becoming resistant to insulin, and developing type 2 diabetes. And if the threat of developing type 2 diabetes isn’t enough to consider changing your lifestyle, maybe learning that it nearly doubles your chances of developing Alzheimer’s Disease will.

It’s time to start spending less time in the McDonald’s drive thru, and more time thinking about your health.

How are Type 2 Diabetes and Alzheimer’s Disease related anyway? The Power of Insulin

Insulin is a hormone that is created in the pancreas that plays vital roles throughout the entire body. Not only does it maintain proper blood sugar levels, but it also assists the body in using and storing energy depending on its metabolic needs. Insulin is what turns your Big Mac into energy that your body can use. 

Insulin Resistance: What happens when insulin can’t do it’s job?: The link between Type 2 Diabetes and Alzheimer’s Disease

So if type 2 diabetes (T2D) is defined by insulin resistance, how does that relate to Alzheimer’s Disease (AD)?

Insulin has a special role in the brain. It works to protect neurons, strengthen connections, and plays vital roles in cognition and memory. If insulin can’t function in the brain, these processes are disrupted.

(Memory loss and impaired cognition are two symptoms of Alzheimer’s Disease)  

The brains of AD patients usually have two main “tell-tale” signs signifying that Alzheimer’s was present: amyloid-beta plaques and neurofibrillary tangles.

It is believed that insulin resistance in Alzheimer’s Disease may be the result of an accumulation of these amyloid beta plaques in the brain, and in supporting this theory, there are many additional hypotheses as to how this insulin resistance develops in the brain.

TNF-α and Inflammation

It is believed that prolonged inflammation is responsible for insulin resistance in both T2D and AD.

In Type 2 Diabetes: As mentioned above, being obese has been linked to the development of T2D. It’s simple: as fat cells accumulate, inflammatory molecules also accumulate, and one of the instigators of this inflammation is a pro-inflammatory cytokine known as TNF-α. 

In Alzheimer’s Disease: Prolonged inflammation is often a defining characteristic in Alzheimer’s brains. This inflammation is often the result of immune cells in the brain known as microglia. These cells often release inflammatory molecules in response to the accumulation of the amyloid beta particles described earlier. Interestingly enough, research has shown that in order for these amyloid beta instigators to cause insulin resistance in AD patients, the TNF-α receptor must be present.

It’s a fairly reasonable conclusion that the inflammatory mechanisms of TNF-α may explain the prolonged inflammation causing inadequate insulin signaling in both AD and T2D.

And there you have it, a link between two unlikely partners in a toxic relationship. 

Figure 1. This image depicts inflammation in the brain and periphery mediated by TNF-α and its relationship to AD and T2D.

Gangliosides and Insulin Resistance

Gangliosides have also been found to play an important role in insulin resistance.

Ganglioside GM3:

Insulin resistance mediated through TNF-α, as described above, is dependent on the accumulation of GM3.

• As GM3 accumulates in the cell membrane, it causes tension that pulls insulin receptors out of their normal location.
  • It is believed that the accumulation of GM3 is the result of amyloid beta plaques interfering with proper ganglioside metabolism.
• When insulin receptors are no longer in the correct spot, they become unrecognizable to the molecules that play a role in insulin signaling.
• When proper signaling can no longer occur, insulin will not be able to perform its functions in the body, and insulin resistance will result.

Figure 2. This image displays the accumulation of GM3 rendering proper insulin signaling defective.

Ganglioside GM1:

The ganglioside GM1 is a binding site for amyloid beta oligomers (ABOs) and is thus responsible for the accumulation of ABOs into toxic amyloid beta plaques. Interestingly enough, research has found that diabetes increases the accumulation of these toxic plaques, and you have yet another link between the two diseases.

So what’s the point?

Stop taking the easy way out when it comes to your health, it could save your life. 

• Take some time instead of the 2 minutes you spend in the drive thru, and make a meal!
  • Here are a few recipes you can try that are SUPER simple, healthy, and relatively quick:
    • “31 Healthy Dinner Recipes that take 30 Minutes or Less”
      • visit: https://pin.it/4ejzhyj6ha7yae
• Stop binge watching Game of Thrones on the couch!
  • You could try watching it on your phone from the comfort of an elliptical or stair climber, trust me, it works!
• Take care of your body; you only get one, and I hate to break it to you, but health care professionals can’t cure every ailment.
  • Just so you are aware: there are no known cures for Type 2 Diabetes or Alzheimer’s Disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996155/

https://www.mayoclinic.org/diseases-conditions/diabetes/symptoms-causes/syc-20371444

https://www.dosomething.org/us/facts/11-facts-about-american-eating-habits

https://www.askdoctork.com/how-does-alzheimers-wreak-so-much-havoc-in-the-brain201506258011

http://diabetes.diabetesjournals.org/content/63/7/2262https://www.healthnutnews.com/alzheimers-type-3-diabetes/

 

 

 

 

 

 

Introduction to autism:

Autism spectrum disorder is a developmental disease that results in impaired functioning in social communication and abnormal behaviors. People with autism generally use less eye contact, fail to know when or when not to use non-verbal gestures, and fail to recognize the emotions of others. Abnormal behaviors seen in autism include but are not limited to repetitive ritualistic behaviors, extreme interests in specific topics, and a need for unvarying routine. While it is difficult to draw the line between a normal and abnormal brain, research has suggested evidence that with autism spectrum disorder there are differences in neurochemical pathways that limit normal functioning of people with the disease.

Environmental causes:

The complex interaction among neural processes associated with autism begins early in development. During pregnancy, even slight changes in the environment can result in tremendous change in the development of the child. A pregnant mother could become infected with a minor pathogen and pass the infection on to the child through the placenta. This transfer may induce a change in the child’s immune response resulting in excess inflammation. Unfortunately, there is only so much preventative action mothers can take during pregnancy. Proper nutrition and avoidance of harmful chemicals and pathogens is all a mother can do to diminish problems with development. It is important for mothers to know that everything they do could in some way affect the baby, but it is also important to know that it is impossible to reduce all environmental risks down to nothing. Along with countless environmental factors associated with ASD, numerous genes have also been identified.

 

Genetic influences:

Thousands of genes have been linked to ASD creating a nightmare for scientists trying to fully understand why this disease occurs. One of the most common genetic abnormalities seen in ASD is a mutation in the MECP2 gene. This gene codes for a protein used in regulating the transcription of other genes. It helps to regulate synapse formation in the brain and makes sure that only necessary connections are made in the brain. People who have an alteration in this gene will have abnormal connections of neurons causing miscommunication among brain domains. Related to this gene is the process seen with the mTOR pathway. In this pathway, unused connections of the brain are removed allowing for normal communication between neurons. This pruning process is essential in normal brain functioning and it thought to be severely impaired in autism resulting in an unusually high density of neurons.

The role of the immune system:

The immune system plays a large role in both in peripheral body tissue and the nervous system. It is used to eliminate intruding pathogens and rid the body of any harmful substances. To do this, a close interaction of T and B cells is orchestrated. T-cells are a type of white blood cells used in initiating an immune response. They release chemicals that cause inflammation and notify the rest of the body where the infection is. These cells are also used in the destruction of harmful pathogens and infected cells. B-cells release antibodies that attach to invading substances and mark them for destruction by T-cells. It is thought that an abnormality of this general process in the brain leads to symptoms associated with autism. Careful regulation of these cells allows normal brains to eliminate harmful substances while preserving delicate brain tissue. In autistic brains, however, regulation of these immune cells is hindered causing excess inflammation. It is this point where many aspects of autism are thought to arise. The extra chemicals in the brain causes excess inflammation without enough regulation. From here, abnormalities in other brain processes are initiated leading to permanent damage during development.

Conclusion:

The pathophysiology of autism is extremely complex and difficult to map out. There are many different aspect of the disease that affect different pathways in neurochemistry. While we do know many of these parts and how they interact with each other, the exact order of events remains unknown. Perhaps genetic predispositions lead to higher probability of in utero infection leading to a malfunctioning immune response in the brain etc. Or perhaps the pathophysiology is much less linear and requires interaction between different processes all at once. Nevertheless, a complete understanding of ASD may never be reached but further research on the disease could provide helpful insight for prevention and treatment of ASD.

Background:

Autism Spectrum Disorder (ASD) has steadily increased over the years. The CDC estimates that autism prevalence will increase to 1 in 59 children in the United States. This is a substantial increase from data in 2004 that showed autism prevalence was 1 in 166 children¹. ASD is a relatively new disorder. Its pathogenesis has eluded scientists since its initial characterization in 1943 by physician Leo Kanner². Since then, ASD has evolved into an umbrella term for a disorder that is characterized by a myriad of behaviors. Repetitive behaviors, impaired social interactions, and language and communications abnormalities are a few of the many different common symptoms of ASD. Although researchers are still unsure of an exact mechanism in which ASD undergoes, they have a few pieces figured out of the complex puzzle that is ASD.

Too Many Neurons, Too Many Connections:

One of the most common findings of different research efforts is that ASD patients suffer due to impaired neural connectivity. This impaired connectivity stems from the significantly increased number of neurons present in autistic patients. The increased number of neurons diminishes the process of shaping and fine-tuning of neural circuits in ASD patients³. The impaired connections in the brain also cause reduced lateralization of the brain which is needed for higher order brain functions. A specific study exhibited that the corpus callosum of ASD patients had increased white matter (from too many neurons), and that this increase in size of corpus callosum inhibited the lateralization of each hemisphere that is used for language production and comprehension³. Simply, there are too many connections between too many neurons which as you can imagine creates too many signals for an autistic patient to comprehend, hence the symptomatic behaviors. This may cause someone to the question: What is causing the increase in neurons and connections seen with ASD?

Precious Pruning:

During “normal” development, cells prune unneeded connections between neurons. Microglia are the cells responsible for this synaptic pruning in babies’ brains. In autism, however, this pruning is not present. Therefore, they have nearly twice as many neurons after development compared to someone without ASD. This leads us to the next question: Why is there no synaptic pruning in ASD? Autophagy is not occurring in ASD brains; therefore, they are not getting a decline in synapses. Autophagy is related to the mTOR pathway, which induces cell growth, differentiation and survival, and down-regulates apoptotic signals and inhibits autophagy. In autism, the mTOR pathway is overactive, inhibiting the process of autophagy. If there is no autophagy, then there is no synaptic pruning, and ultimately leads to an excess of neurons. Researchers have then studied genes and risk factors during development to cause the lack of pruning.

Genetics Role in Autism:

After extensive research, it is clear that many certain genes and environmental factors contribute to the development of autism. There is no “autism gene.” However, there are affected genes that fit into several clusters that may underlie ASD. Mutated NLGN3/4, SHANK3, NRX1 genes alter the synaptic function and lead to autistic disorders such as Asperger’s syndrome³.  Other strong contributors to ASD are TSC1/2, PTEN, and NF1 which are associated with autophagy and the mTOR pathway. Finally, another cluster of genes that control gene transcription and translation are related to the pathogenesis of ASD. Mutations of these genes are hypothesized to cause a loss of normal constraints on synaptic activity-induced protein synthesis. This specific loss may be one of the several mechanisms leading to ASD.

Summary:

Autism’s complicated umbrella is covering many families across the world. Understanding ASD will be more important than ever as we see its prevalence increasing across the United States. Although it is a very complex disorder, pieces have been placed together by researchers. Many genes affect ASD. In my mind, it makes the most sense focusing on the specific cluster of genes including TSC1/2, PTEN, and NF1. Mutations in these genes, which are associated with the mTOR pathway, could cause over-activation of this pathway. If the mTOR pathway in ASD is overactive, it inhibits the process of autophagy. This causes a lack of synaptic pruning, which proceeds by microglial autophagy. If microglia are inhibited, a build-up of neurons and connections between these could occur. The increased connectivity and neurons cause the symptoms associated with ASD. These are not all of the pieces to this puzzling umbrella disorder, but it is a starting point to understanding ASD.

 

1. https://www.autismspeaks.org/science-news/cdc-increases-estimate-autisms-prevalence-15-percent-1-59-children
2. https://www.spectrumnews.org/opinion/viewpoint/leo-kanners-1943-paper-on-autism/
3. https://moodle.cord.edu/pluginfile.php/723245/mod_resource/content/0/pathophys%20of%20ASD%202017.pdf