Alzheimer’s disease, the most common form of dementia, is characterized by a gradual and then quickening and irreversible loss of memory and cognitive functioning, with associated behavioral changes.
Gerontologist Laura Wayman says: “I tell family caregivers that they need to start thinking of a loved one’s brain like a piece of Swiss cheese, which has random holes in it. The disease is robbing them of brain cells that allow them to function normally.” She explains that when a person with Alzheimer’s tries to access the functionality of their brain, they may either access “cheese” (a lucid moment), or a “hole” (a confused moment in which they frantically try to compensate for memory loss with bizarre behaviors, often linked to feelings and memories from their past).
According to the National Institute on Aging, during the very early stage of disease, people with Alzheimers’ disease do not show any symptoms — however, during this time, several changes take place in the brain. Abnormal deposits of proteins form amyloid plaques and tau tangles throughout the brain. Consequently, once-healthy neurons begin to work less efficiently. Amyloid plaques are the build up of sticky proteins called beta amyloid, and tau tangles are twisted strands of a protein called tau. Over time, neurons lose their ability to function and communicate with each other, and eventually die. Before long, the damage spreads to a nearby structure in the brain called the hippocampus, which is essential in forming memories. As more neurons die, affected brain regions begin to shrink. By the final stage of Alzheimer’s disease, damage is widespread, and brain tissue has shrunk significantly.
However, deposits of amyloid plaques and tau tangles are only some of the numerous changes present in individuals with Alzheimer’s disease. In these individuals, disease progression is also associated with altered brain immune responses, and especially with a type of immune cells called microglia.
Microglia are the resident macrophages of the central nervous system. They play a significant role not only in the healthy brain, where they support neuronal integrity, but also in the diseased or injured brain. Indeed, they’re known as the brain’s garbage collector — microglia scavenge dead cells, infectious microorganisms, and other debris.
Now, results from a new study carried out in a mouse model suggests that, in Alzheimer’s disease, microglia begin to abnormally consume an important nutrient: arginine. In the study, blocking the over-consumption of arginine with the small drug difluoromethylornithine (DFMO) prevented the development of the characteristic brain plaques and memory loss.
For the study, the researchers analyzed different cell types and found that microglia are the only cells that divide and change early in the disease — they found an increase in the expression of genes associated with suppression of the immune system, and they also found decreased expression of genes that work to activate the immune system.
Matthew Kan, the study’s first author, said in a press release: “It’s surprising, because suppression of the immune system is not what the field has been thinking is happening in Alzheimer’s disease. Instead, scientists have previously assumed that the brain releases molecules involved in ramping up the immune system, that supposedly damage the brain.”
The researchers blocked arginase using DFMO — and therefore disrupted the pathway responsible for the utilization of arginine — before the onsets of symptoms in the mice. Blocking of arginase resulted in a decrease of microglia and plaque development in the mouse brains, and in better performance on memory tests.
DFMO is being investigated in human clinical trials to treat some types of cancer, but it hasn’t been tested as a potential therapy for Alzheimer’s disease. Now, the researchers are conducting experiments in mice to determine whether or not DFMO can be effective in treating the characteristic signs of Alzheimer’s disease after they appear.
Carol Colton, senior author of the study, said in the press release: “We see this study opening the doors to thinking about Alzheimer’s disease in a completely different way, to break the stalemate of ideas in Alzheimer’s disease. The field has been driven by amyloid for the past 15, 20 years and we have to look at other things because we still do not understand the mechanism of disease or how to develop effective therapeutics.”
The video below shows the intricate mechanisms involving amyloid plaques and tau tangles in the progression of Alzheimer’s disease in the brain.
It has been shown that Arginine plays an important role in effectiveness of the immune system. Arginine has been shown to stimulate T cell proliferation and release into the blood stream as well as increasing the number of thymic T lymphocytes. In a study of mice fed a diet with Arginine, showed that arginine correlated with improved T cell function than mice without the arginine diet. Arginine has also been shown to be a major substrate for macrophages. They use arginine to produce nitric oxide, which kills bacteria and parasites as well as activates other immune cells.
Perhaps as the microglia are consuming large amounts of arginine they are releasing nitric oxide, which in large amount, could cause the amyloid plaques and tau tangles.
Alzheimer’s is a terrible disease that can tear families apart. It is terrible to witness a loved one losing their mind. Preventing the buildup of the plaque and sticky proteins sounds very beneficial to helping prevent the neurons from not functioning normally. The harm of the microglia is a critical factor since they are the immune response system in the brain. It could be possible that using the DFMO to block arginine and the use of anti-inflammatory drugs could reduce and maybe even prevent the symptoms. The anti-inflammatory drugs have the potential to change the metabolic pathways in the brain. It is extremely interesting that Alzheimer’s is caused by a decrease in efficiency of the immune system. If it works in the mice, moving on to human testing would be the next best course of action. I feel like there would be a lot of people willing to be used in a clinical trial. And end to this terrible, mind-altering disease would save many families so much heartache and stress.
To me it seems as though decreasing microglia activity in the brain could be a double edged sword. Microglia secrete proteins that are able to breakdown amyloid plaques. They also rid the brain of foreign materials or dysfunctional cells. It appears as though the underlying theory to the progression of AD stems from chronic inflammation in the brain, which can be caused by the activation of microglia in response to the presence of the buildup amyloid plaques. While using DFMO to suppress microglial activity is interesting, it could lead to other complications for the central nervous system. As with any new science, more research is needed and I think the world could benefit by funding research such as this.
It is very interesting to discover that Arginine could play such a critical role in the development/prevention of the infamous Alzheimer’s disease! Also, I am astounded to learn that the body’s immune system decaying and becoming suppressed could be a trigger or tell to signify that Alzheimer’s disease has begun its gradual path. If it is true that an increase in Arginine could lead to an increased immune system, and by preventing Arginine destruction/absorption by microglia the symptoms of Alzheimer’s are delayed, then it could be theorized that perhaps an Arginine based treatment plan could be enacted to help offset the decay of the immune system and thus, by extension, Alzheimer’s itself! If there was some sort of screening procedure that could detect possibly low or lowering amounts of natural Arginine that is being produced by the body, then that would be the perfect chance to influx a prepared dose of Arginine to counteract the loss of immune system responses due to loss of natural Arginine. Maybe certain dosages over time would allow for a greater opportunity to set a better foundation to protect the brain and its cells from the eventual decay they experience! These treatments could of course be tested in mice to see how their immune system responds and then correlate the data with what information gathered already over the course of medical history to potentially create a dramatic difference in the fight to prevent/cure Alzheimer’s!
2) Even though microglia resident cells provide defense mechanisms of immune responses to protect the central nervous system, they are considered the causative agent leading to Alzheimer Disease due to their phagocytosis function. These cells are involved in signaling the accumulation of amyloid plaques and Tau tangles and that in turn lead to the activation of more microglia. One wonders how the microglia cells are evoked in the initially to make them scavenge the brain’s nutrients and as it turns out that there are several influences. One certain factor that I believe is reason for activating excessive number of microglia cells is the homeostasis imbalance in the brain region when certain genes are expressed to suppress the immune system while other genes that support the immune system are not expressed. Once microglia cells detect the imbalance in brain, they disrupt the levels of produced arginine amino acids and that causes neurons to decompose thus losing their ability to communicate.
Here I have found a picture that shows a numerous activation of the microglia cells around brain regions.
It is very interesting how much we continue to learn about the diseases that affect the body. Hopefully, framing Alzheimer’s disease as a part of an immune disorder will cause a shift in the imaginations of scientists and bring forth the discovery for a cure of a very serious disease. DFMO sounds promising, but it is also important to determine what causes the abnormality in the microglia. If microglia detect an imbalances and begin to have altered function, what causes that imbalance? Is it genetic? Is it spontaneous? Is it simply something that occurs with old age? I believe that more research is required in this area as well.
Indeed it is interesting to find out this new information in regards to Alzheimer’s and a possible treatment. My concerns though are the possible long term affects of using DMFO as an inhibitor. In this article it stated that The researchers blocked arginase using DFMO — and therefore disrupted the pathway responsible for the utilization of arginine. If new research is showing that the brain’s immune response can be linked to Alzheimer’s would it be wise to inhibit the use of such a vital cell to our bodies? In the paper The Bacterial Twin-Arginine Translocation Pathway it states The twin-arginine translocation (Tat) pathway is responsible for the export of folded proteins across the cytoplasmic membrane of bacteria. Substrates for the Tat pathway include redox enzymes requiring cofactor insertion in the cytoplasm, multimeric proteins that have to assemble into a complex prior to export, certain membrane proteins, and proteins whose folding is incompatible with Sec export. These proteins are involved in a diverse range of cellular activities including anaerobic metabolism, cell envelope biogenesis, metal acquisition and detoxification, and virulence. Can the body really function if this pathway is disrupted?
I am blessed to still have a set of great grandparents and a great grandmother on the other side still living. Unfortunately, in the past couple of years, one of my great grandmothers has been dealing with dementia. I loved the opening analogy the doctor provided for what the patients experience during this time.
I too am very intrigued by this information of the degenerate disease. I never knew one of the amino acids I was responsible for memorizing would play such a major role in this disease or any of the above mentioned. I agree with the concern of the long-term and overall body response to DMFO as being used as an inhibitor. The research presented above demonstrates that nothing in the body works in isolation. So disrupting this one component definitely interrupts a whole network. For sure further research should be funded with this information. I also liked the screening idea for the triggers to detect the pre-symptom diseased brain. Presented by another commenter.
The problem with these drugs is that although we are eager to find treatment, we have to be aware of long-term effects of a drug. Does the benefits outweigh the costs? It is shown that DFMO is not as effective as it may seem as treatment. Because it is irreversible, it would be interesting to see what effects it leads to long term. Also, it was found to be toxic at high dosages, but it is not all bad. DFMO is being tested and is reportedly more effective as a preventive agent of cancer.
Here is the link for more information on the study:
http://www.ncbi.nlm.nih.gov/pubmed/10353725
Alzheimer’s disease the forgetting gene an article mentioned that a neurologist Warren Strittmatter in 1991 was studying on amyloid-β which is the main component in the brain of people suffering from Alzheimer’s disease founded a compound called apolopoprotein E (ApoE) has no connection with disease. But in later findings it was considered as one of the important component of the disease and helped in making various drugs.
Many scientist are working on the way to diagnose the symptoms related to this disease at very early and if that is possible like biomarkers or any brain imaging technique like PET scan, MRI etc, any blood test technique or any genetic mutation involved in the disease will help a lot to find the disease at early stages and person with the diagnosed disease can be helped.
It would be interesting to see the relationship between microglia and oligodendrocytes. We are able to see that oligodendrocyte dysfunction can cause the creation of tau tangles and amyloid proteins. If there isn’t the formation of both tau and amyloid, would there be a reduced progression towards Alzheimer’s disease (AD) that would alter the brain’s immunological response that causes microglia to abnormally consume arginine?
Also, what role does arginine play in demyelination. We know that there is a breakdown of myelin that can be seen in AD patients. If there isn’t, maybe arginine is a consequence later in duration of AD as loss of myelin is usually associated with the early stages of AD. That would mean with arginine, we are focusing in on a consequence of the latter stages and could already have extensive damage done to make the brain “swiss cheese” like.
Memory impairment and cognitive dysfunction associated Alzheimer’s dementia, epilepsy and concussions are contingent upon the role of the immune system. A recent study has a found a protein that serves as a biomarker for brain damage, it is called S100B. S100 calcium binding protein B (S100B) is found only in the brain and spinal column and can leak through the blood-brain barrier upon acquiring a head injury.
Entry of S100B into the blood-brain barrier activates the immune system, which in turn release antibodies to opsonize the protein. Contact sports become mediators that trigger and autoimmune response against the brain, which inevitably result in neurological diseases. A research study sought to question, whether the presence of S100B in the extracranial tissue is as a result of antigen-presenting cells in the blood, which induces the production of auto-antibodies. The testing was carried out using animal models of seizures, patients undergoing repeated disruption in the blood-brain barrier, and a collection of blood samples from epileptic patients. If finding show that there is S100B in the extracranial tissue, therapeutic treatment for brain injury may include “anti-inflammatory or immunomodulators to decrease the autoimmune response.
Another publication in Newsweek, 2000 explained that scientists were :
So I find the swiss cheese analogy to be in bad taste. I know very little about alzheimer’s. I have never had a loved one forget so drastically, but I imagine it to be heart-breaking. The brain is a large network of neurons. When a chunk of the connective network is removed, it may feel like something is there, perhaps like when you have something on the tip of your tongue. Dr. Wayman says they compensate their 404 error with other memories and emotions which would result in weird behavior. Judging by the video, there isn’t specific targeted spots, but as a whole the brain is affected. Wherever these plaques and tangles group is where the cells will begin to die, so this makes me wonder, the more cells you may have devoted to an aspect of your life, will these memories be the last to go? I wonder if new information is forgotten first?