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Insulin: not just about diabetes

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Insulin – a hormone involved in more than just Diabetes

Type 2 Diabetes

Image from: https://theconversation.com/diabetes-new-test-could-detect-the-disease-much-earlier-101409

Type 2 diabetes is a chronic condition that affects how the body processes glucose. Insulin is the molecule that allows glucose to enter the body’s cells. The cell breaks down glucose to produce energy. In type 2 diabetes, the body cannot produce enough insulin, or it resists insulin. In both cases, the blood will be too concentrated with glucose, leading to hyperglycemia. This is the mechanism that produces type 2 diabetes, but is there another disease that has insulin resistance as a factor?

Alzheimer’s Disease

Image from: https://www.spectrumhealthlakeland.org/lakeland-ear-nose-and-throat/ent-health-library/Content/85/P00772/

Alzheimer’s disease (AD) is the most common form of dementia, characterized as a progressive disease of memory loss, mood changes, disorientation, confusion, behavior changes, loss of physical functions, and an overall decrease of brain functioning. On the inside, neurofibrillary tangles, and amyloid -plaques are observed as key changes to the brain. Both of these phenomenon cause brain cells (neurons) to die.

Picture from: https://ucsdnews.ucsd.edu/pressrelease/novel-drug-prevents-amyloid-plaques-a-hallmark-of-alzheimers-disease

The neurofibrillary tangles are an abnormal accumulation of a protein, tau, that is hyperphosphorylated (too activated). Normally, tau supports the structure of the neuron by stabilizing microtubules which help guide nutrients and molecules down the cell. In AD, hyperphosphorylated tau detaches from the microtubules and stick to each other, forming tangles that block the neuron’s transport system from inside the cell.

Amyloid-beta plaques are clumps of beta-amyloid proteins that collect between neurons disrupting communication and inducing cell death. The accumulation of beta-amyloid proteins is in part due to an increase in the activation of the pathways that produce it. But how does tau become hyperphosphorylated and how do beta-amyloid pathways become activated? This is where insulin can be an answer.

Insulin in the Brain

Insulin regulates glucose metabolism. The brain requires a constant abundance of glucose as it is the most active part of our body and, thus requires a great amount of energy. As seen above, insulin controls glucose channels to allow glucose uptake by the cell. However, in the brain, the glucose receptors that allow glucose intake into most brain cells are independent of insulin. They do not need insulin to open up.  So why does the brain need insulin?

Insulin appears to be important for the regulation of food consumption behavior and monitoring energy stores. Insulin is a strong neuroprotective agent that acts against apoptosis, -amyloid toxicity, and oxidative stress. Insulin contributes to the control of nutrient homeostasis, reproduction, cognition, and memory.

But, what happens if the body becomes resistant to insulin like in Type 2 Diabetes?

Insulin resistance (IR) induces the degradation of insulin-degrading enzyme (IDE), a key enzyme for clearing -amyloid proteins. IR activates the MAPK signaling pathway (an important brain pathway) which stimulates the amyloidogenic pathway and inhibits the non-amyloidogenic pathway leading to the accumulation of -amyloid. These malfunctions together lead to the formation of amyloid- plaques.

A drawing done by Alison Amundson

Additionally, IR decreases the activation of the PI3K/Akt pathway. Without this pathway being activated an enzyme called GSK3 is activated and phosphorylates tau. Another enzyme known as PP2A is inhibited by IR, which leads to tau phosphorylation. These two mechanisms combined instigate neurofibrillary tangles to form. A summary of these mechanisms is shown in figure 4.

Why should we care?

Alzheimer’s is a disease that affects millions of patients every year, and it’s not just the individuals with a diagnosis that are affected. Families, friends, nurses, doctors, administrators, and more are subjected to the hardships that come with AD.

If insulin resistance can be named as a risk factor for AD development, we can increase our arsenal of knowledge for how to decrease the severity of AD symptoms and push back the onset age.

But type 2 diabetes is linked to obesity. Obesity is concurrent to the overindulgence of unhealthy food and a low physical activity level. If obesity leads to insulin resistance, then obesity can lead to AD.

Image from: https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet

Therefore, eating right and maintaining a steady level of physical activity to avoid gaining weight can also lessen your chances of developing AD pathology and symptomology. So, the next time you reach for your fifth candy bar of the day or bail on your third walk of the week, think about how your brain could turn into this:

 

 

References:

https://doi.org/10.3389/fnhum.2020.602360

https://doi.org/10.1016/j.neuint.2020.104707

https://doi.org/10.1155/2015/105828

 

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Yes, it is that bad!

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It is alarming at this point the growth rate of neurodegenerative diseases, in both young and older people. Take Alzheimer’s Disease, for example, it is highly known for being related to aging but now knowing the underlined link it has type II diabetes the concern grows even bigger. Though largely targeting persons in mid-60s and beyond, various factors were contested as the potential causal factors including genetics, infections, age, etc. However, the actual cause is still unknown.

Senile Stock Photos & Royalty-Free Images | Depositphotos

It is the most common form of dementia and among the top ten leading causes of death in the United States.

The direct cause of Alzheimer’s is still unknown but various factors that contribute to several of its symptoms have been identified, which is very helpful in practicing prevention.

Symptoms

Amongst the most common symptoms of AD, including memory loss, confusion, mood fluctuation, and others. These symptoms were found to be largely caused by the impairment of insulin regulation, which further causes neuroinflammation that results in neurodegeneration in multiple regions of the CNS.

In the study reported by Proceedings of the National Academy of Sciences, researchers used a novel mouse model to understand the impact of insulin resistance in the occurrence of the symptoms above. This was done by blocking the expression of insulin receptors and related Insulin Growth Factor1, critical regions of the brain for learning, memory, and mood.

The regions targeted were the amygdala and the hippocampus, to study effects on glucose, anxiety, and cognition. The defects observed were largely related to the impaired expression of GluA1 NT.

In a review article, Insulin Signaling Pathway and Related Molecule, insulin resistance’s effect on AD is further explained to the way it causes neuroinflammation and neurodegeneration. Key players here include the GSK3-b which impacts positively in the formation of pro-inflammatory cytokinesis, such as IL-6, that bind to stress-activated cytokines, which inhibit the phosphorylation of tyrosine in IRS. This cause an impaired insulin regulation.(Akhtar, 2020)

What now?

Uffda! The point is,  it is important that as a society we take major steps to practice preventative methods, to largely avoid risks of type II diabetes which has been shown to increase the risks of AD. This can be done by adopting a healthier diet, exercises, developing means to keep the brain active.

Alzheimer disease risk factor and prevention poster vector - 108974049

 

Moreover, there have to be better ways to develop means to accommodate those who have AD and ease them in that process. Help them with day-to-day activities, promote muscle memory (playing piano) keep reminders for their memory and help them keep in touch with their loved ones.

Caregivers need care too!

This attention is necessary as well to the caregivers of the people with AD. Given the contested symptoms that AD patients have, it is very frequent that they may get physical or really disrespectful to their caregivers. This can eventually take a toll on one’s mental health, and physical health, which makes it necessary to create a support system for caregivers to keep them grounded and feel appreciated.

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Alzheimer’s Disease Post

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There are many interesting scientific topics that can be very informative to the public. There are many that are worth learning about and one that the public should make an effort in learning more on are diseases that result in inhibition and blockage of receptors in the brain. One of these diseases is called Alzheimer’s Disease. According to the CDC, Alzheimer’s disease is one of the most common types of dementia that affects the parts of the brain that control thoughts, language, and memory [1]. The risk of Alzheimer’s increases with age with almost six million people living with Alzheimer’s as of 2020 [1]. So far, research on Alzheimer’s is currently ongoing with more information learned each day. 

A recent study on Alzheimer’s was done by looking at how Insulin signaling pathways and other molecules affect the progression of Alzheimer’s in people. It was learned that Insulin pathways in the brain, normally controlling the clearance of amyloid Beta and tau metabolism, can be blocked by the presence of a repressor protein [2]. This blockage’s outcome is the development of resistance against Insulin, which would then lead to Alzheimer’s Disease.  

However, there are ways that the body can prevent Alzheimer’s from occurring. There is more than one pathway that contains inhibition and activation enzymes occurring within the brain that influences the progression of Alzheimer’s disease. One pathway through Insulin signaling is with Phosphatidylinositol 3-kinase (PI3K) presence. PI3K is a serine/threonine protein kinase that is responsible for the activation of Akt, an oncogene responsible for maintaining cellular functions like metabolism, transcription, protein synthesis, proliferation, growth and survival of neurons [2]. The activation of Akt would then lead to the phosphorylation inactivation of GSK-3 Beta, a serine/threonine-specific protein kinase with multiple signaling processes, such as insulin signaling pathways [2]. Since GSK-3 Beta is an important factor in Alzheimer’s development, it’s inhibition caused by PI3K is important. If GSK-3 Beta was not inhibited, this would lead to tau phosphorylation and increased assembly of amyloid plaques causing symptoms of dementia and cognitive impairment [2]. With all these steps in mind, this shows that PI3K is an important factor to stop the development of Alzheimer’s disease. 

While these factors play a significant role in Alzheimer’s disease, Alzheimer’s can also be caused by factors in a person’s life that are not just medical. For example, traumatic or stressful events happening in a person’s life could increase their chances of getting Alzheimer’s [3]. Such events could include being fired from a job, divorce from a significant other, witnessing combat, declaring bankruptcy, and the death of a family member [3]. These factors show that an increase in anxiety levels or stress can lead to Alzheimer’s progressing at a faster rate. This is more evident in further studies on Alzheimer’s disease.  

As depicted in the study, inhibition of insulin signaling pathways causing neurodegenerative processes linked to the progression of Alzheimer’s, and other diseases such as Huntington’s and Parkinson’s [3]. It would be very beneficial to learn more about how Alzheimer’s affects a person from both external factors that are in the form of stressful scenarios for the person and internal factors that are within the person’s body.

  1. https://www.cdc.gov/aging/aginginfo/alzheimers.htm
  2. https://www.sciencedirect.com/science/article/pii/S019701862030098X?via%3Dihub 
  3. https://www.alzheimers.net/the-stressful-life-events-that-can-lead-to-alzheimers
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Alzheimer’s Disease 101

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Dancing Against Alzheimer’s Disease

My favorite video on the internet is of an elderly woman, who once was a ballerina, doing the upper body movements for one of the pieces she performed in the Swan Lake ballet. As a former ballet dancer myself, I enjoy hearing the music and watching others dance to it. Now, I don’t just love this video because it is ballet, but I love this video because the woman dancing has Alzheimer’s Disease. If you want to watch the video, which I totally recommend you do, the video is linked here.

Basics of Alzheimer’s Disease

In case you are unfamiliar with Alzheimer’s Disease, I will provide a brief crash course. There will be a quiz at the end of it, so make sure you’re paying attention. Just kidding. Alzheimer’s Disease is progressive disorder that leads to severe memory loss. Alzheimer’s Disease is biologically characterized by the death of neurons (brain cells) and abnormally decreased brain mass. The death of neurons tends to be linked to two things: amyloid plaques and neurofibrillary tangles. These words sound a little scary, but I will try to help them make sense.

Amyloid Plaques

Amyloid plaques are formed from beta-amyloid proteins, which are naturally occurring in the brain. These proteins, in an Alzheimer’s Disease brain, clump together and form a large mass between neurons multiple neurons.[1] With the beta-amyloid mass impeding on cell function and communication, the neurons begin to die.[2]

Neurofibrillary Tangles

An image of tau as a net.
Fig. 1. An image of tau sticking together to form a sort of net that blocks nutrients from passing throughout the neuron. Drawn by H. Almlie.

Neurofibrillary tangles are similar to amyloid plaques in that they both are an abnormal accumulation of protein. Where amyloid plaques are caused by the accumulation of beta-amyloid proteins, the neurofibrillary tangles are caused by an accumulation of proteins called “tau.” It helps to think of neurofibrillary tangles like nets made out of tau, as pictured below. The tau proteins, which are found inside of the neuron, stick to each other to block the transport of nutrients from the neuron cell body to the other side of the cell.[3] So, I know that was a lot of information thrown at you but, to sum it up, amyloid plaques and neurofibrillary tangles are both present in Alzheimer’s brain and are both a build-up of proteins outside of the cell (plaques) and inside of the cell (tangles).

 

What Causes Alzheimer’s Disease?

An image of the insulin-signaling pathway.
Fig. 2. An image of the insulin-signaling pathway and the changes to the pathway seen in Alzheimer’s Disease. Drawn by J. Mach, copied down by H. Almlie.

Now, you may be asking yourself, “What causes Alzheimer’s Disease?” You pose an excellent question, and this is something I wondered as well. Researchers don’t know for sure what causes the buildup of these proteins, but many of them speculate it is a result of improper intracellular communication in the insulin signaling pathway. Again, I know this may not be a familiar topic, but I will try to explain it the best I can. To do this, I think it helps to have an image. The image below gives a brief rundown of the insulin signaling pathway and what changes are seen in brains with Alzheimer’s Disease, and I will talk you through what is going on in the image.

Insulin Signaling Pathway and Why it Relates to Alzheimer’s Disease

Usually, a hormone called insulin binds to a receptor in the brain, which is portrayed by the field goal post at the top of the image. The hormone binding to its receptor then triggers an intracellular communication pathway that starts with a protein called the insulin receptor substrate (IRS). Activation of this protein leads to activation of an enzyme with the acronym PI3K, which then signals activation of two different molecules: an enzyme referred to as Akt and a protein called mTOR. When Akt is activated, it inhibits glycogen synthase kinase (GSK-3B—another enzyme). In Alzheimer’s Disease, however, this entire pathway is abnormal. Firstly, there is less insulin binding to the receptor in brains with Alzheimer’s Disease due to something called insulin resistance. Because less insulin is binding to the receptor, there is less activation of IRS, which creates a snowball effect that leads to less activation of PI3K, then decreased activation of mTOR and Akt. Because there is less activation of Akt, GSK-3B is not inhibited as much as it should be. It is at this point where the two protein build-ups that I discussed previously can be explained. Therefore, because GSK-3B is not inhibited, activity is increased and leads to the formation of neurofibrillary tangles and amyloid plaques as a result of neuroinflammation. This is a very simplistic explanation but following along with Fig. 2 is helpful in wrapping your mind around what is happening.

[1] https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease

[2] https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease

[3] https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease

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Top 3 ways to care for loved ones affected by Alzheimer’s Disease

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What is happening in the world of Alzheimer’s?

Alzheimer’s Disease (AD) is affecting individuals and families all over the world, and numbers suggest that it is a rapidly growing problem in all of society. Recent studies have found that abnormalities in insulin signaling have some major effects on AD, which is why it has been linked to Type 2 diabetes. But first, we we’ll look at some of the basics.

Artstract by Zsofia Zelenak

Why is this happening?

Biochemists have the tendency to scramble the alphabet, pick a few letters, sometimes even add some numbers, put them in a seemingly random order, and at times finish up with Greek symbols. They will then assign these to proteins of various sizes and complicated pathways in our bodies, such as mTOR, Akt, MAPK, Grb, GSK-3β, and so on. Should you want to try and do the same, all you need is a quick PhD and you yourself could easily move from scrambling morning eggs to scrambling those ABCs in lab.

Now, I brought these complex molecules up for a reason, which is the fact that they all participate in the insulin signaling pathways shown above, making up an important part of the disease. When we say Alzheimer’s, what we really think of in a molecular level is lots of cell death and overall neuroinflammation. Sounds awful, right? Let’s take a look at why these two things might be happening:

  • buildup of amyloid- β plaques
  • neurofibrillary tangles (NFTs) present
  • overactive MAPK, GSK-3 β
  • underactive Ras, Akt, mTOR
  • questionable action of Grb

How do we care?

At this time there isn’t a way for us to know who exactly will be diagnosed later on, so much of what science can offer for those concerned is a shot at prevention. The general public is encouraged to try and prevent the disease by making healthy lifestyle choices and training our “cognitive muscles”. Other than prevention, the sad reality is that once symptoms are showing there is little we can do. Here, I am talking to those who are simply curious, or eager to care for their loved ones, but have little idea on how to do it best. I have gathered the top responses to the question “how would you want to be cared for?” from our neurochemistry paper discussion and listed them below.

Top 3 ways to care for Alzheimer’s patients:

  1. Have patience

The most common answer in our discussion circle was to have people surrounding you that have lots of patience. Most of us love and need frequent social interactions, even if certain circumstances, such as cognitive and memory impairment, make it harder than usual.

  1. Don’t push the newest reality

As an interesting second came the idea of just letting one live in their own world. Some students expressed that sometimes it might be exhausting to be presented with a completely new reality to you than the one you might be existing in inside your head. This idea really just comes down to letting patients rest and go with their own world without challenging it.

  1. FAQ binder

For our creative ones we also got a DIY project on the list. I will have to say, it was also one of my personal favorites I sided with, and I mean, who didn’t love the ending of the movie 50 First Dates? Yes, it is a glorified representation of memory struggles, but why not use it to our advantage? Some of us just tend to lean towards logical reasoning and maybe would enjoy having an organized binder full of answers. It could include things such as bullet points of basic information (when/where/who/how), show pictures of close family and friends, and give short summaries of current conditions of the world. For those who question most things in life, this might be a quick relief as they get to have the answers right at their hands all in one place.

 

 

Sources:
1. Akhatar, A., & Sah, S. P. (2020, February 18.). Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease. Neurochemistry International. https://www.sciencedirect.com/science/article/abs/pii/S019701862030098X?via%3Dihub
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Should I care about Alzheimer’s? Yeah probably….

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Artstract by: Alex Braun

Artstract by: Alex Braun

Protein basics

To understand how to help prevent yourself from developing Alzheimer’s disease, it helps to have some background information about the disease. Alzheimer’s disease is thought to be caused by the abnormal buildup of proteins in and around the brain cells. One of these proteins is amyloid, deposits of which form plaques around brain cells. The other protein, tau, deposits of which form tangles in the brain cells (NHS et al., 2021).

 

Amyloid Plaques

Amyloid is a protein fragment that the body produces naturally.  Amyloid plaques are hard, insoluble accumulations of beta amyloid proteins that clump together between the neurons. The reason these plaques are hard to dissolve in the fluid between cells is because the enzyme that cuts the amyloid precursor protein (APP), cuts strands that are too large. Since these strands are too large, they are “sticky” and start clumping into deposits which are referred to as plaques (BrightFocus et al., 2020).

NFT and Amyloid plaques: comparing a normal brain with an Alzheimer’s diseased brain.

Neurofibrillary tangles

Neurofibrillary tangles are insoluble twist fibers primarily consisting of the protein, tau. These tangles form when tau is misfolded in a peculiar way. Specifically, in Alzheimer’s disease, tau forms a C-shape in the core in the core of the tangle with a loose end sticking out randomly. Once a tangle has been started, more tau proteins are recruited to make it longer (BrightFocus et al., 2020).

 

This all sounds scary, so how can one help prevent developing Alzheimer’s disease

Well, it’s not exactly as simple as just “do this and you won’t get Alzheimer’s” because life would be too easy if that was the case. You can however, live a healthy lifestyle and keep an active brain to help reduce your chances of developing Alzheimer’s disease

 

Cardiovascular and Alzheimer’s

Cardiovascular disease has been linked with an increased risk of Alzheimer’s disease. You can reduce your risk of developing both cardiovascular disease and Alzheimer’s disease by not smoking, drinking alcohol in moderation, eating a balanced diet, and exercising (NHS et al., 2021). I know this sounds redundant to say, but seriously, just live healthy and you’ll be better off.

Stay healthy to help prevent developing Alzheimer’s

Staying mentally active

There’s some evidence to suggest that rates of dementia are lower in people who remain mentally and socially active throughout their lives. One may be able to reduce their risk of Alzheimer’s disease by reading a book, learning a new language, playing an instrument, group sports, being social (NHS et al., 2021) One could also play “brain training” computer games which haven’t been fully proven to prevent Alzheimer’s, but who knows, you might even have some fun.

 

Other factors

Factors that are not directly responsible for Alzheimer’s disease but play a role in development include hearing loss, untreated depression, and loneliness (NHS et al., 2021) So, if you know someone who is lonely or depressed, go be their friend so you can help them reduce their risk of developing Alzheimer’s.

 

Works cited

Amyloid plaques and neurofibrillary tangles. BrightFocus Foundation. (2020, March 13). Retrieved from https://www.brightfocus.org/alzheimers-disease/infographic/amyloid-plaques-and-neurofibrillary-tangles.

 

NHS. (2021, July 5). Causes of Alzheimer’s Disease. NHS choices. Retrieved from https://www.nhs.uk/conditions/alzheimers-disease/causes/.

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Signaling in the Brain is The Tightest Regulation Around

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Have you ever felt like you are following too many rules in your life, or that you have too little control in major life events? This phenomenon is all too common, but in the brain specifically it takes regulation and rules to a whole new level. In the brain it is dangerous to have both too much or too little of many chemicals and proteins, so much so that diseases such as Alzheimer’s disease can be cause both by too much or too little of certain chemicals that our brain depends on for normal function.

What is Grb and What Does it Do?

Grb is one of many vital proteins in the brain, and it is part of the MAPK pathway. This pathway is one of the most tightly regulated pathways due to its ability to both help and inhibits the usage of insulin in our brains. There are two separate mechanisms of insulin: regular insulin signaling and the competition against insulin, where MAPK performs exactly the same function in two different environments.

Breaking down the two pathways; too little normal signaling can be compared to a traffic stop where the light is green and there is a car not proceeding. When that car is not moving, the entire normal pathway is slowed and insulin can’t perform its vital functions in the brain. On the other hand, when the competitive insulin pathway is overstimulated, the situation is similar to a traffic junction where a car blows a red light and starts to cause a traffic jam in the intersection. In this case, too many “cars” in the signal pathway causes a blockage that prevents insulin from doing its job in the brain. Notice how in the two images below the left pathway (MAPK) never changes, but the end result is two entirely different impacts on the insulin binding site. More on Grb and these pathways

Why is this blockage bad?

When insulin is blocked in the brain, there is a wide host of problems that can occur, one of those many problems is the beginnings of Alzheimer’s disease. Many studies have linked Alzheimer’s disease to the inability to properly regulate insulin. Due to the above pathway obstructions (both too little normal signaling and too much competition), insulin will build up and cause a hyperglycemia in the brain. This buildup of sugar leads to the two telltale signs of Alzheimer’s disease; amyloid beta plaques outside the neurons and phosphorylation of a dangerous tau protein inside the cells. These work together to cause irreparable damage to the brain, specifically the neurons that help transmit information. Individuals infected with Alzheimer’s see a substantial drop in their cognitive function, which leads to major quality of life impacts. Once this destructive pathway becomes active, there isn’t much we can do to stop it with current technology outside of treating the symptoms and placing the individuals under the care of another person as their own capacities begin to fail.  This demonstrates how important it is to follow the rules and regulations of the brain, even if you don’t necessarily follow all the rules outside the brain. More on insulin and Alzheimer’s Diesase

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Exploring the Caspase Family in Alzheimer’s Disease

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An Overview of Alzheimer’s Disease: 

Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by progressively worsening executive cognitive functioning, including memory impairment and overall cognitive deficits. The symptoms start small and may not even be noticed but for the following years, the disease will become much more apparent. Hyperphosphorylation of the tau protein causes the production of neurofibrillary tangles and amyloid-beta plaques, which trigger neuroinflammatory pathways, eventually leading to neurodegeneration/apoptosis, decreasing brain size. Frontiers | The Role of P2X7 Receptor in Alzheimer's Disease | Molecular Neuroscience

The Caspase Family:

The caspase family includes caspase 1-12 and are all protease enzymes that play significant roles in neuroinflammatory and pro-apoptotic processes. As proteases, these enzymes (caspase 3, 6, and 7) break down proteins into peptide chains, then further into individual amino acids.

The inflammatory caspases (1, 4, 5, 8, and 11) initiate the inflammatory response after a pro-inflammatory cytokine binds to the corresponding receptor. Different caspases communicate with each other to transduce the cytokine’s signal to the cell nucleus, where pro-inflammatory gene transcription is upregulated, leading to higher degrees of cell inflammation. In terms of AD, inflammatory caspases can aggravate the neurofibrillary tangles and amyloid plaques, which can trigger neurodegenerative processes, eventually leading to apoptosis. 

Crystal structure of Caspase-3 (3DEI), the caspase gaining most attention as a possible therapeutic target

The pro-apoptotic and neurodegenerative caspases (2, 8, 9, and 10) are responsible for initiating the apoptotic pathway, leading to the breakdown of various proteins inside the cell into peptides and amino acids, which can lead to the neuron or cell becoming nonfunctional, which triggers programmed cell death pathways. This explains why post-mortem analyses of AD brains are significantly smaller in size than non-AD brains.

The figure below illustrates this idea of how NFT/AB plaques, neuroinflammation, and neurodegeneration are all related through the caspase proteases. https://pubmed.ncbi.nlm.nih.gov/31111399/

Apoptosis and Neurodegeneration:

It is important to note that caspase-mediated neuroinflammatory and neurodegenerative pathways are not themselves impaired in AD progression. Caspases do not like neurofibrillary tangles or amyloid plaques. Their interaction stimulates cytokine release and the pathway that follows responds the way it is supposed to. These proteases are behaving exactly the way they are meant to, but the dysfunction of the upstream pathways is constantly triggering these events.

Can we Treat AD with Caspase Inhibitors?

The short answer is yes, but it may not be a very effective therapeutic aspect in terms of “curing” Alzheimer’s. The formation of neurofibrillary tangles and amyloid-beta plaques is a required prerequisite for hyperstimulating pro-inflammatory cytokine release and thus neurodegeneration and apoptosis. These steps are consequences far downstream from severe kinase pathway dysfunction and developing successful caspase-targeted drugs would not do anything to stop or retard the progression of the disease.

Caspases are at the end of the signal transduction pathway. The progression of AD is not a simple, one-road track. This disease is caused by severe dysfunction of nearly every protein involved in an already complex signal transduction pathway. The caspases are far downstream from these proteins and their actions are a result of chaotic impairment of upstream functioning. Developing a caspase inhibitor could marginally increase the cell lifespan, but in terms of AD pathogenesis, it would do nothing to prevent the disease from progressing. This paper goes further into the neurochemistry of caspase-mediated apoptosis in AD and explains caspase-targeted drug outlook more in-depth. https://pubmed.ncbi.nlm.nih.gov/11556539/

Summary

Caspases are largely responsible for inflammation, neurodegeneration, and apoptosis in Alzheimer’s Disease. While their specific pathways are not dysfunctional themselves, their activity is a result of dysfunction throughout upstream pathways that lead to tau hyperphosphorylation. As proteases that are towards the end of the AD-progressing pathway, using them as drug targets could prolong cell life and may increase cell lifespan at best, but the progression of the disease is much more complicated.

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