Cobbers on the Brain

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

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?

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

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).

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.

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/.

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.

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.

We’ve spoken quite a bit about the impacts that amyloid plaque can have on the anatomy of our brains, and subsequently how those changes in anatomy can have negative effects on our cognitive function. But in case you forgot I will provide a brief overview. Plaques accumulate over time naturally, however, in Alzheimer’s our brain fails to keep up with the demand for clearance and is therefore overwhelmed by the buildup of these plaques. The abnormal levels of these plaques clump together and are found positioned between neurons, ultimately disrupting cellular function as shown below (U.S. Department of Health and Human Services). 

Consider for a moment that we could simply remove these plaques, it may not solve our problem entirely but perhaps it could lead to a decrease in negative symptoms momentarily. Lucky for us the advancement of technology has provided new techniques to not only decrease amyloid plaque formation initially, but to potentially remove it from an area entirely after is has begun to accumulate. 

It might be helpful to first provide some background information that is required to understand the topic. Embedded within an amyloid plaque lies a protein called APOE. APOE is located near the center of the amyloid-APOE complex and is accessible from the exterior given the right circumstances. These complexes come together with AB Fibrils, proteins that are initially soluble but become insoluble after their assembly is altered, this combination is what forms the amyloid plaques that we are so used to talking about. You can see this without my poor explanation in the figure shown below.

Changes in APOE proteins are thought to be one of the largest risk factors for Alzheimer’s, different unnatural changes to the protein can lead to differing severities of the disease. The figure below demonstrates the negative side effects that can come from the unnatural variations of APOE. 

Researchers at Washington University recently discovered antibodies that can target and initiate removal of plaques from the brain by directly binding to the APOE domains. By doing this the antibodies effectively flag the compound for degradation by the local immune system. Although it is meant to be a humorous take on the immune systems response to APOE, the picture that I altered may help you remember this point. 

When these immune cells target the APOE, scientists discovered that the immune cells would also carry away the connected amyloid plaque that had formed around the APOE. In this situation you can think of the APOE-plaque complex as the metaphorical saying “throwing the baby out with the bathwater,” except in this case it’s a positive.

It should be noted however, that there is a caveat to this claim relating to the removal of plaques via antibody binding. Scientists believe that using antibodies may only be effective during the early stages of amyloid plaque build-up. The scientists from Washington noted that if too much plaque is present, that the addition of antibodies might not be enough to counteract the inevitable disease that is Alzheimer’s.

“Okay,” you might say, “but surely APOE has other important roles in the body, degrading all of it would be bad.” And indeed you would be right, APOE does have other important roles in the body such as “the transfer of cholesterol and phospholipid between cells” (Liao et al, 2017). Luckily however, researchers found an antibody that only affects the APOE in the brain and not throughout the rest of the body. Initially the researchers were stumped as to why the antibody (antibody HAE-4) only affected the APOE in the brain. But of course, someone else had done their research for them, it turns out that there are three different naturally occurring isoforms of APOE. Different isoforms are present depending on the region of the body, the brain having its own individual isoform entirely (from what I gathered from the article). This difference allows antibodies, and therefore researchers, to target the brain’s APOE without worrying about damaging the subject. Because of this discrepancy, researchers can potentially use antibody technology to prevent Alzheimer’s disease in the future.

Sources

Liao, F., Yoon, H., & Kim, J. (2017, February). Apolipoprotein E metabolism and functions in brain and its role in Alzheimer’s disease. Current opinion in lipidology. Retrieved September 27, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5213812/.   

ScienceDaily. (2018, March 26). Antibody removes alzheimer’s plaques, in mice. ScienceDaily. Retrieved September 27, 2021, from https://www.sciencedaily.com/releases/2018/03/180326161000.htm.  

U.S. Department of Health and Human Services. (n.d.). What happens to the brain in alzheimer’s disease? National Institute on Aging. Retrieved September 27, 2021, from https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease.