To be honest, I did not know much about Nitric Oxide (NO) before reading the scientific paper on the topic for our neurochemistry class. All I could have told someone is that it is important for vasodilation and that body builders take it as a workout supplement to get more blood pumping (supposedly to help them build muscles faster).
This week though, I got to make some pretty cool connections between this toxic NO buildup from microglial cells and Alzheimer’s disease. I’ll go over some basics and then reveal the connections.
The Basics
Alzheimer’s disease:
This is the most common form of dementia and is characterized by progressive mental deterioration as people age. One main issue in Alzheimer’s disease is the aggregation of amyloid plaques between nerve cells in the brain.
This makes it hard for the cells to communicate properly and puts them under a lot of stress.
Nitric Oxide:
In people and other animals, NO is an important cellular signaling molecule in the right amounts. It is a powerful vasodilator and keeps the blood vessels open and lowers the amount of plaque in them.
Too much however, can damage brain cells and help to increase inflammation in the brain. This is seen in many neurodegenerative diseases such as Parkinson’s disease, Huntington disease, ALS, and Alzheimer’s disease.
Microglia:
This type of cell makes up the brain’s immune response and accounts for 10-15% of the cells in the brain. They respond to neuronal damage and remove the damaged cells by phagocytosis.
When they are activated however, they cause an inflammatory response which can lead to a cascade of damaging events in the brain.
Putting It All Together
Through this paper we read on NO and inflammation, I found out that microglia actually MAKE amyloid precursor protein in response to injury from too much neuronal excitation. Remember that buildup of amyloid beta is what causes the plaques seen in Alzheimer’s disease.
When the amyloid precursor protein is abnormally cut, it makes the amyloid plaques.
This process stimulates inflammation, toxins, and nitric oxide production which damages and kills the brain cells even more.
The extra damaged cells make more microglia activate to get rid of the damaged cells – which creates more nitric oxide, more inflammation, and more amyloid beta plaques as seen in Alzheimer’s disease.
The image below is an overview on the never ending cycle I just described.
It’s terrifying to think that our own body’s reaction to cell damage can cause even more damage. Most of the time microglia are helpful and don’t harm other neurons, but when we age – this is a cascade that is happening to many adults when they get Alzheimer’s disease.
More research needs to be done and is being done on how to stop this process from starting in the first place.
The Role of Nitric Oxide in Alzheimer's Disease
You have learned in a semester what I pieced together in a decade.
The main problem in Alzheimer’s disease is that an excess of nitric oxide and superoxide anions are being produced at the same time–resulting in a very reactive oxidant called peroxynitrite. Through tissue damage and inhibition of glutamate uptake, peroxynitrite increases inflammatory reactions in the brain. The release of glutamate in combination with its limited (re)uptake activates microglia–the immune cells in the brain. The microglia in turn produce more peroxynitrite.
It is possible that in some cases, peroxynitrite inactivates microglia, so Alzheimer’s disease may not be a case of rampant inflammation in the brain (New Findings on Brain’s Immune Cells during Alzheimer’s disease progression and Peroxynitrite Inhibits T Lymphocyte Activation and Proliferation by Promoting Impairment of Tyrosine Phosphorylation and Peroxynitrite-Driven Apoptotic Death). Peroxynitrite can through DNA damage and preventing the down-reguation of the phosphatidyinositol 3-kinase/Akt pathway lead to the rise and spread of cancer cells and at the same time allow those cells to escape immune responses. The problem in Alzheimer’s disease is the reverse: peroxynitrite by inactivating the neuroprotective phosphatidylinositol 3-kinase/Akt pathway leads to the death of neurons and may allow amyloid to escape immune responses (this is not likely a problem, though, as amyloid does not cause Alzheimer’s disease).
The peroxynitrite invocation of caspase-3 leads to the first cut of the amyloid precursor protein by BACE1, the release of intracellular calcium leads to the second cut in the amyloid precursor protein leading to amyloid oligomers, and the peroxynitrite-mediated nitration of amyloid oligomers leads to the production of amyloid plaques. All of this is secondary however to excitotoxicty and cell death via a loop that includes NMDA receptor activation and peroxynitrite formation.
The compounds that best inhibit peroxynitrite formation are polyphenols found in various fruits, vegetables, spices, and drinks. The best compounds for scavenging peroxynitrite and partially reversing its damage are methoxyphenols (ferulic acid and syringic acid in panax ginseng and eugenol in various essential oils via aromatherapy, for example).
http://www.ncbi.nlm.nih.gov/pubmed/22780999
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/
http://onlinelibrary.wiley.com/doi/10.1111/j.1479-8301.2009.00299.x/full
The answer to Alzheimer’s disease is right at our finger tips. Maybe someone from this class will make that breakthrough. In memory of my cousin, aunt, and mother, I hope so.
Alzheimer’s disease is close to my heart as well! Before this paper, I’d looked into other aspects of the disease and not specifically on NO. It is definitely a key aspect in the degenerative properties of the disease. Clearing the plaques and the tangles in the brain – that’s what most of my research in my undergraduate has been directed towards. I’m glad I now have this piece of information as well. The PI3K/AKT pathway and how it relates to all of these prominent diseases was probably the most important thing I learned about in this class. If we could only figure out the starting point and how to better intervene…. hopefully in the near future! Thanks for your input!
Thank you very much for your reply here and on one of your other posts. The PI3K/AKT is indeed one of the most critical pathways for health and disease. Too much activation can lead to cancer. Too much inhibition of this pathway can lead to a series of neurodegenerative diseases. Thus, probably the likely explanation for the observation that people who have cancer rarely develop Alzheimer’s disease and people who have Alzheimer’s disease rarely get cancer.
Cell death and cell growth are finally balanced in the human body. When that balance gets thrown off by various environmental toxins, genes or genetic mutations, stress, diet (high sugar, high carbohydrate, high sodium, high fructose corn syrup), and certain medications illness can eventually ensue.
The main starting point for the PI3K/AKT pathway are receptor tyrosine kinases (including insulin receptors) and g protein-coupled receptors. The cascade that the activation of these receptors triggers can be inhibited by various polyphenols in fruits, vegetables, spices, and drinks. That is why a Mediterranean diet is recommended both for reducing the risk of cancer and Alzheimer’s disease (as well as being good for your heart). Many of these polyphenols are not particularly bioavailable and they might not be able to offset all the risk factors for cancer and Alzheimer’s disease, but they are at least a start.
I cannot put my finger on why I enjoy reading these entries so much. Maybe because I am a history instructor I appreciate how students engaged and passionate about subjects can add to knowledge. Maybe because I have an interest in understanding the causes and treatments of various diseases, I like seeing the clear and helpful ways the students in this class approach this big topic. Or maybe I just like seeing how much they have learned and gotten out of the experience. In any case, I wish you and all the other graduating seniors the best as well as to all those who are continuing their education at Concordia or elsewhere.