Alzheimer's Vaccine?

Alzheimer’s Vaccine

Alzheimer’s disease and dementia are among several of the neurological degenerative disorders affecting more than three million US citizens per year. The vast majority of neurodegenerative diseases are not inherited. Often trademarked by cognitive decline, delusion, disorientation, and difficultly in recognition, these disorders typically affect geriatric patients. Brain cells are destroyed, connections are severed, and eventually mental function is no longer able to be processed. There is no cure currently; however, symptoms are managed with medication and cognitive exercise. Research is underway in regard to the trafficking and convergence of neurons. Dr. Subhojit Roy shared his work and the endeavors he hopes to accomplish in this population.

In the journal, “Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway,” he explained that patients with Alzheimer’s disease typically present with an accumulation of beta-amyloid plaques. The plaques make transportation of the neural signals difficult, and eventually the pathways are no longer maintained. Thus, the patient experiences symptoms concerning their mental processes. CRISPRs, standing for Clustered Regularly Interspaced Short Palindromic Repeats, are tools used to “cut” the DNA strand. They are used to edit the genome, a way to engineer the genetic code in hopes of eliminating the gRNA strands responsible for contributing to the disease. Although Dr. Roy did acknowledge two concerns of editing the APP including off-target and physiological consequence, the research data showed that the use of CRISPRs aided in restoring the transportation in the amyloidogenic pathway of the two proteins: APP and BACE-1. The convergence of the two proteins convergence is a low frequency event in resting states but increases under conditions of neurogenesis. 

Gene therapy is being studied in addition to using CRISPR in the treatment of neurodegenerative disorder. Gene therapy is the transplantation of normal genes where defective genes once were. I recently read an article, “Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease” The study involved transplanting nucleic acid to cognitively normal patients who possessed the apolipoprotein E allele, a common gene linked to Alzheimer’s disease. Candidates who were given the primary prevention therapies (nucleic acid) were observed to have much lower rates of symptoms pertaining to Alzheimer’s disease. In addition, PET scans were used to obtain glucose levels in areas of the brain such as the prefrontal cortex, basal forebrain, and thalamus.

Dementias, including Alzheimer’s disease, are among the most common neurodegenerative diseases worldwide. Through various therapies such as CRISPR, gene therapy, and medication we can seek to provide patients options when treating the symptoms of the illness. Removing and replacing the defective genes seems to be the most promising way of treating symptoms. In the future, my opinion would be that studies the effects of tau will reveal even more information to help us understand the pathogenesis and components of neurodegenerative disorder.

References:

“The Physical Approximation of APP and BACE-1: A Key Event in Alzheimer’s Disease Pathogenesis” Jichao Sun.Subhojit Roy.Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, 1111 HighlandAvenue, Madison, Wisconsin, 53705.

“Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease”

Eric M. Reiman, Richard J. Caselli, Kewei Chen, Gene E. Alexander, Daniel Bandy, Jennifer Frost

Proceedings of the National Academy of Sciences Mar 2001.

Revival of our Tastes

Our sense of taste is an expression of ourselves. It lets us experience the world, savor the different cuisines, and live pleasurably. Imagine if you could no longer taste anything. Surely, a great part of our happiness is taken away- the happiness brought to us by tasting and sharing food with loved ones. The scientific term for the loss of taste is called ageusia. This condition is not so much physically serious as it is mentally. The loss of taste causes individuals to be severely depressed, leading to great mental impact. Loss of taste is usually also accompanied with the loss of smell- our pathway for taste and smell are greatly linked. These two senses not only function in merely tasting food and smelling odors, but more seriously, taste and smell are interconnected with memory and learning. Certainly, all of us have specific tastes and smells that cause us to recall memories. Losing these senses, therefore, have far greater impacts than quality of life.

             Ageusia can be attributed to various factors. Serious conditions causing ageusia include oral cancer, brain damage and injuries due to stroke or radiotherapy, or surgery performed in the ENT area that has damaged nerves essential for gustatory senses. Natural aging can cause decrease sense of taste, although usually not complete loss. There are also various forms of taste disorders besides ageusia which include hypogeusia, dysgeusia, and phantogeusia, all of which are caused by the lack of proper function of the gustatory nerves and system. Certain forms of these disorders are hard to cure- especially if the loss of taste is due to an autoimmune disorder or genetic conditions. However, information on gustatory signaling pathway can help us develop a drug that patients which such conditions can take in order to increase innervation of the gustatory nerves.

             Dr. Rochlin’s study, “Ephrin-B/EphB Signaling Is Required for Normal Innervation of Lingual Gustatory Papillae”, makes exciting discoveries on the gustatory pathway which expands our knowledge on key mechanisms, allowing us to apply this information in a clinical setting to develop a solution to disorders such as ageusia. This study discovers that proteins EphB1 and EphB2 are essential for proper and necessary gustatory innervation of the mammalian tongue. It is stated that this study provides the first evidence for the role of ephrins in the lingual gustatory epithelium and the discovery that EphB proteins are expressed in taste axons. It also highlights the requirement of ephrin-B/EphB for normal innervation of papillae. The results of Dr. Rochlin’s study contributes greatly to our knowledge of the gustatory pathway and allows further research to be continued to discover yet greater details of human gustatory senses. Furthermore, these results allow scientists to research into developing drugs that increases Eph-B proteins which are required for proper innervation of the papillae for patients with ageusia. If such a drug were developed, patients that have lost their sense of taste to oral cancers or aging have a chance of recovering their senses via pharmaceuticals.

             In the article by Science Daily titled, “Regenerating lost taste buds: Key steps discovered”, another important protein that plays a great role in developing taste buds was discovered. The beta-catenin protein is part of the Wnt pathway which regulates separate stages of taste cell turnovers which then controls the renewal of taste cells. Activating the Wnt pathway can be a solution to renewing taste buds that are destroyed or altered by chemotherapy for cancer patients. Since chemotherapy destroys precursor cells which turn into the various taste cells, this pathway can help restore proper function in patients receiving chemotherapy for oral cancers, thus reinstating their sense of taste.

Combining the results from this study as well as Dr. Rochlin’s study that emphasizes the role of EphB proteins in the gustatory pathway, the development of a drug that regulates taste dysfunction and restores taste in patients that are aging or have lost the ability to taste due to oral cancers is in the very near future. This is great news and a new-found hope to those who suffer from ageusia since restoration of their sense of taste will not only allow for a better quality of life but a better mental state.

References:

https://www.sciencedaily.com/releases/2015/05/150528142813.htm

http://www.bbc.com/news/magazine-23051270

The Cure to Not Aging Well

           Many people would choose to live a shorter life if it meant living a high quality and healthy life for the entire duration. Alzheimer’s disease takes this away from millions in the United States and even more globally. The thought of not being able to remember our life experiences, our loved ones, and even simple everyday tasks is truly brutal and a force to be reckoned with. During his talk, Dr. Roberto Fernandez-Romero explored the relationship this disease has with aging. He explains that he wants to find new markers for the disease because it’s important to learn about the path of physiology when studying a disease. This neurodegenerative disease doesn’t affect the entire brain equally. It affects particular areas of the brain that are more specific to the disease, lot of which have to do with memory. With this we can see the progressive gradual decline of cognitive function. He emphasizes that over 5 million people in the United States alone that suffer from this disease currently and that this number will probably rise to 15 million within the next few years. What’s even more shocking is that of 10 the leading causes of death, Alzheimer’s is the only one that cannot be prevented, cured, or effectively treated. 

In the article, Alzheimer's from a New Angle, Alice Price explains how “Globally, nearly 50 million people are living with dementia, most of which is caused by Alzheimer's, and absent effective drugs or other interventions, that number is expected to double every 20 years.” (Park, 2016) So, what is the source of all this? Dr. Fernandez-Romero went into detail on how the proteins Beta-Amyloid and Tau maintain microtubule structure and transport, but when these proteins start to malfunction, they form plaque in the brain. This plaque then ends up blocking transmission at the synapses, which results in the alteration of activity in the brain. (Fernandez, 2012) It’s important to ask what causes the changes in amyloid and tau, but at the moment we aren’t sure why these proteins change and how they change. Dr. Frank Longo, like many others is also trying to take steps in the right direction in hopes of a cure for Alzheimer’s. As the chairman of the neurology department at the Stanford University School of Medicine, Dr. Longo specializes in memory disorders and regularly sees patients whose brains are slowly diminishing. Since the year 2000 over 200 drugs have been tested in hopes of curing the disease, but none have been successful. “My biggest frustration is that we've cured Alzheimer's in mice many times. Why can't we move that success to people?" Dr. Longo says. (Park, 2016) It’s a step in the right direction that scientists have figured out how to eliminate the amyloid plaques in animals, but doing this in humans has really been a brainteaser. 

In his research, Dr. Fernandez-Romero had subjects perform driving tests where they had to remember how to get to and from particular locations. His goal was to “identify distinguishing effects on neural mechanisms related to driving and navigation”. (Fernandez, 2012) Parietal lobe function and the perceptual basis of navigation are an ideal model to study aging and Alzheimer’s disease. He explained that as a clinician, one of the biggest problems that he sees with his patients is related to driving. Patients that have early stages of Alzheimer’s sometimes don’t know that they have these symptoms and having to tell them they can’t drive anymore is very difficult. Not every city has public transportation like Chicago. He said giving them data helps them accept that they may need to give up this life skill in order to stay safe. It’s safe to say that part of the problem here includes figuring out when older people need to be screened for the disease, because obviously everyone isn’t taking part in clinical research that shows if they’re in the clear to operate motor vehicles, or something similar. 

While Dr. Fernandez-Romero and many others look into various details to help Alzheimer’s patients live better lives, Dr. Longo started a drug company, which is now on phase II of the clinical trials for a new drug that is very promising. This drug is noteworthy compared to others, because it worked on the mice and confronts Alzheimer's in a different way than any drugs that came before it. The new drug, LM11A-31, takes a much less traditional approach to solving the problem. Rather than going after every source of amyloid, the goal is to “keep brain cells strong, protected against neurological onslaughts, whether they're the effects of amyloid or other factors involved in Alzheimer's”. (Park, 2016) Dr. Longo emphasizes that he, along with many others are working to find ways to eliminate the “amyloid plaques that start to accumulate like molecular garbage in certain corners of the Alzheimer's-afflicted brain” (Parks, 2016).

Some people may believe that most people, who live a long life, will suffer from some form of dementia, but the hope is that this notion can be wiped out. While some of us wait on a miracle, it’s reassuring to know that people like Dr. Fernandez-Romero are finding ways to help people deal with this and people like Dr. Frank Longo are going off the unbeaten path to look at untraditional approaches for the cure. Hopefully, soon people won’t need to choose the option of living a shorter quality filled lifestyle, and will instead be able to live a long life-span filled with top quality health. 

References

Fernandez, R., & Duffy, C. J. (2012). Early Alzheimers disease blocks responses to accelerating 

self-movement. Neurobiology of Aging,33(11), 2551-2560. doi:10.1016/j.neurobiolaging.2011.12.031

Park, A. (2016, February 11). Alzheimer's From a New Angle. Retrieved May 2, 2018, from 

http://time.com/4217067/alzheimers-from-a-new-angle/

Mother vs. Father

Mother vs. Father 

By: Christian Roque 

When it comes to the battle between the sexes, it seems like females have won before the battle even started. As humans grow older, some end up getting diseases, disorders, and other long-term effect, positive and negative. With these long-term effects, there are also short-term effects that occur in our lives as well. It has just been recently studied that long-term effects actually come from the mother, while short-term effects come from the father. An article published by Scientific American explains how this came to be. 

The article states that a recent study published in The Conversation by senior author Arunas Radzvilavicius and co-author Andrew Pomiankowski found that the inheritance of mitochondrial genes come from the maternal mitochondria. Radzvilavicius found that females secrete enzymes that degrade the paternal mitochondrial genes while the sperm enters the egg. What he also found was that there are some paternal mitochondrial genes that are not degraded and are passed on to the offspring. Interestingly, he also found that in some organisms, the father himself destroys most of his mitochondria. 

Radzvilavicius stated that through mathematical model, he found that it is the maternal mitochondrial genes that focus on long-term effects, while paternal mitochondrial genes focus on the short-term effects. He says that it decreases harmful future mutations when destroying paternal mitochondria. So, while the males try to improve their offsprings short-term, the females try to free their offsprings from their paternal mitochondrial genes. 

This study is parallel to Dr. James Cheverud’s study in maternal genotypes affecting adult offsprings. In his study, he and his team focused on the lipid, obesity, and diabetes phenotypes in LGXSM recombinants. Not only did they find a correlation between the maternal genes and the offspring, but also the environment the mothers give their offspring affects them as well. His team did find, though, that with age the effects of maternity decreases. Radzvilavicius’ study can give Dr. Cheverud and his team some optimism with their idea that maternal effects are long-term. While Dr. Cheverud and his team did see that decrease, maybe they didn’t wait long enough for those long-term effects to kick in. Also, Radzvilivacius focused on mitochondrial genes, not the genes that affect lipid, obesity, and diabetes phenotypes. Both Dr. Cheverud and the study in Scientific American focus on maternal genetic affects on offspring, but they both still have much more to learn, and they can learn from each other in hopes of understanding how exactly our mothers’ genetics affect us long-term. 

Reference: 

Radzvilavicius, Arunas L. “It's Mostly Mothers Who Pass on Mitochondria.” Scientific American, The Conversation, 5 Nov. 2017, www.scientificamerican.com/article/it-rsquo-s-mostly-mothers-who-pass-on-mitochondria/.

ALZHEIMERS 

Recently, various different neuroscientist have come to our seminar to demonstrate their great research, however, to me, two main researchers made a personal connection. Those two professors were Dr. Fernandez-Romero and Dr. Roy. What caught my attention from these two researchers, is that both study Alzheimer’s Disease. My family has a history with Alzheimer’s and so it was very interesting listening and reading about their findings. 

Before I proceed to discuss the work of Dr. Fernandez-Romero and Dr. Roy, it is important to note what Alzheimer’s truly is. Alzheimer’s disease is a neurodegenerative disease that progressively deteriorates mental functions such as memory. Alzheimer’s usually has an onset at a later stage in life, usually middle to old age. As I learned in Dr. Fernandez-Romero’s lecture, Alzheimer’s used to be constantly confused with old age dementia. Scientist used to believe that as people grew old, they lost mental function progressively. However, this changed when Dr. Alois Alzheimer realized that this was an actual neurodegenerative disease, as it only occurred in some elderly people and not others. This discovery initiated the constant research to find the cure for Alzheimer’s. 

Although both studied revolved around Alzheimer’s disease, both have different perceptions on the disease. Alzheimer’s has been a recent topic in modern time, as it continued to grow in diagnosis. Recently, the Alzheimer’s association stated that Alzheimer’s is the 6^thleading cause of death in the United States and up to 5.7 million Americans are diagnosed with it. This being stated, it is important to further understand the biochemical aspect of what is occurring when Alzheimer’s develops.

In Dr. Roy’s study, he begins by discussion how the development of plaques in the brain, caused by the presences of a protein named amyloid beta, can be a indicator of Alzheimer’s. This development of plaque is caused by the cleavage of a protein named amyloid precursor protein (APP). The protein that cleaves APP is named BACE-1. Once APP is cleaved, it proceeds to develop amyloid beta, which as previously stated, induces plaque growth. According to the Alzheimer association, plaques can further proceed to block cell signaling at the synapse. Dr. Roy research was focused on the pathways of APP and BACE-1. He wanted to see if any dysregulation of these proteins in their pathway would further induce the production of plaques in neurons. Through his research, Dr. Roy was able to study specific regulators that are responsible in handling APP and BACE-1. As further research still needs to be composed, it is still important to understand the underlying biochemical aspect of Alzheimer’s.

As we further understand our biochemical understanding, it will give a further insight on how it affects the human body. In Dr. Fernandez-Romero’s research, he studied how Alzheimer patient respond to different virtual driving environments. He set up two different controls (young age group and old age group) and then the experimental group was early Alzheimer’s patients. All three groups then participated in a virtual driving test. Through this they experience various different stimulus. In his experiment, he used event related potentials, specifically N200, to measure the change in different environmental stimulus. What he was able to find with the N200 potentials was that, although Alzheimer patients performed well in the increments in motion, they had a significant change in their responsiveness to acceleration. Even compared to the old age group, the early Alzheimer patients had a lower response to the increment in speed. This shows how even at an early stage of Alzheimer’s, it still has an impact on your day to day life tasks.  

In 2017, the New York Times released an article titled, “What if You Knew Alzheimer’s Was Coming for You?”Which discusses various topics about Alzheimer’s disease. The article began with a story of Julie Gregory, she was caught off guard when she was diagnosed with having two recessive genes that could lead to Alzheimer’s. She was diagnoses when she had her gene sequenced to see if why she had poor circulation. Unfortunately, the test demonstrated her having a gene ApoE4 that is linked to the diagnosis of Alzheimer’s. The article continued to proceed with various stories on how people who have a high possibility to obtain Alzheimer have been reacting to their potential diagnosis. The article underlying message is diagnosis. No one knows if someone is truly going to obtain Alzheimer’s until plaques actually being to build up. However, many people are not even aware that they are at risk of Alzheimer’s just like how Julie was unaware. As one could notice in Dr. Roy’s research, diagnosis is not truly set and stone, as the pathways for various proteins are still being developed. However, because this field is still developing, simple pretesting is not available for the average person. In the article we learn that to find out whether a person is at risk for plaque development, they have to go through a PET scan or a spinal tap, which imposes high risk and cost. Philanthropists such as Bill Gates, have begun to donate money to further biochemical research, such as Dr. Roy’s, to develop a more accessible test for the average person. We continue to see in the article how a young woman also found out she was at risk for Alzheimer’s. She talked about how she had to change her life style to adapt to her potential disease. She even gave further insight on how her father, a neurologist, had to change his lifestyle as well. This brings up the importance of Dr. Fernandez-Romero’s research. As stated previously, his research focused on the changes that patients goes through when they preform day to day activity such as driving. It is important for people to be able to adequately and affordably determine whether they are at risk for Alzheimer’s disease. As studies such as Dr. Fernandez-Romero have shown, it imposes a very dangerous situation to people who have early Alzheimer’s, and with lack of diagnosis, it could lead them to damage their health in the future. Overall, I think that I have a better understanding of what Alzheimer’s is due to these two great researchers and as time proceeds, further information will be known to how to deal and cure this disease. 

Driving Alzheimer's Disease Away

 Cressalynne M. Ligo

           For the second half of the semester, Dr. Roberto Fernandez-Romero came to present his research on the effects of early Alzheimer’s disease on driving and navigation. In order to do this, researchers created three groups: young normal control subjects (YNC), older normal control subjects (ONC), and patients with early Alzheimer’s disease (EAD). One of the tests included a virtual driving test. Subjects from each group were asked to watch video sequences that were previously recorded from a vehicle moving at about 20 mph. From these video sequences, the researchers created 2 types of video stimuli: pattern coherence and motion speed. Both types had various speeds at which they were played at. The results were measured based on Event Related Potentials (ERPs). Researchers found the virtual driving test evoked N200s with large responses in both the coherence and speed trials. It was found that in the speed portion of the test those in YNC had larger responses at all speeds, but those in EAD had little any responses. There were no clear results for those in the ONC.

            In a similar study done by Hird and colleagues (2016), researchers sought to analyze two subject groups and their driving abilities. The study attempts to distinguish whose driving ability is better or worse between people who have Alzheimer’s disease versus people who have mild cognitive impairment. In order to avoid any constructs, three groups were made: very mild Alzheimer’s disease, mild Alzheimer’s disease, and mild cognitive impairment. All subjects were given a variety of tests including on-road test scores, pass/fail classifications, caregiver reports, real world crash involvement, and driving stimulator collisions/risky behavior. Researchers found that those with very mild and mild Alzheimer’s disease failed an on-road test compared to healthy drivers. In contrast to the first group, those with mild cognitive impairment demonstrated minor driving impairments. Based on these results, researchers were able to conclude that driving ability is affected based on the degree of cognitive impairment. Cognitive impairment results varied due to dependence on severity whereas the results of the group with the disease were consistent.
            Both studies attempt to explain the correlation between Alzheimer’s disease and driving ability. The first study uses a virtual driving test to measure both the subjects’ coherence and speed during the stimulation by comparing those with Alzheimer’s disease to people who were of different ages. The second study uses an on-road test along with a variety of other tests to measure the difference in driving abilities between people with the disease versus people with cognitive impairment. Although both have different characteristics, they both attempt to analyze the correlation that the disease might have with a person’s driving ability as well as navigation skills.

Sources:

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad160276

https://www.sciencedaily.com/releases/2016/07/160713103538.htm

Alzheimer's: Every Mystery Has Its Solution

I believe that medical mysteries are something that will never cease to exist. No matter how much advancement we have in technology, there are some things that we can never get to the bottom of. But when we do figure out a 50 year long disorder, disease, or even just a question, it is something that will forever be remembered. There are hundreds of thousands of extremely intelligent individuals out there that are trying to solve some of the world’s most complicated mysteries that take the lives of millions of people each year.

The mystery of Alzheimer’s is something that has left thousands of doctors and other medical professionals scratching their heads. As the years go on, the data and clues begin to stack up and eventually it will begin to point to a certain direction. Dr. Subhojit Roy is making great advancements in figuring out what exactly is going wrong in the brain of patients with Alzheimer’s. Over 5 years of research of the disease has led him to discover that patients with Alzheimer’s, they have an over accumulation of amyloid beta, an endogenous protein that is in our bodies. This over accumulation of amyloid beta in the human brain then causes insoluble deposits to form, more commonly known as plaques. These plaques is one of the main characterizations that we see in all patient’s with Alzheimer’s. Dr. Roy was able to find a way to possibly stop the synthesis of amyloid beta through the use of CRISPR-Cas9 to edit the genome. Through the use of CRISPR-Cas9, we may cut out the specific sequences that regulate APP and BACE-1, precursor proteins and enzymes are responsible for deriving amyloid beta, thereby preventing the formation of these insoluble deposits.  

This is a huge step in figuring out Alzheimer’s and possibly finding a treatment that may slow, eradicate or even prevent the onset of the disease. However, even though we may have found a possible treatment for the disease, the actual cause of Alzheimer’s is still uncertain. Recent studies have shown that sleep deprivation may be linked to Alzheimer’s. Drs. Ensan Shokri and Nora D. Volkow have recently found that sleep deprivation in mice causes an increase in Amyloid-beta that cause the plaques that we seen in Alzheimer’s patients to form. Even though that this was only tested in mice, researchers believe that they will see similar results in human trials. This might be another huge step in terms of prevention and a way that we can easily utilize to lessen the chances of developing the disease.

Through the work of Dr. Subhojit Roy, Dr. Ensan Shokri, Dr. Nora D. Volkow and thousands of other researchers and doctors that are trying to solve the mystery of Alzheimer’s, are growing closer to the solution by each day that goes on and its only a matter of time before we see a breakthrough. Every mystery has its solution. 

ARTICLE: https://www.sciencedaily.com/releases/2018/04/180413155301.htm