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Aloysius Alzheimer
Since Alois Alzheimer first reported his findings to South-West German Society of Alienists, plaques and tangles have become synonymous with the disease named after him. And yet, no one really knows how or why they are connected. In fact, very little is known about why these rogue proteins form, if they are the disease’s cause or a symptom, or if medical science will ever be able to control them. New evidence, however, indicates that there may be a connection between the immune system and Alzheimer’s.
Beta amyloid (Aβ) plaques and neurofibrillary tangles are both, basically, “misguided” proteins. Both form from natural proteins that perform necessary functions in the brain. It is when these proteins malfunction that plaques and tangles cause their own sets of problems.
Whereas plaques are sticky proteins that accumulate between brain cells, tangles accumulate within the cell body. Plaques and tangles are known as hallmarks of Alzheimer’s in that they are always present in the disease. Both eventually cause cell death, but the relationship between the two is not well understood. Getting a handle on that might help apply the brakes to the runaway train that is the Alzheimer’s epidemic.
Alzheimer’s disease is the sixth leading cause of death in the United States. Currently, 5.5 million people in the US have the disease, and the worldwide figure is 44 million. Even though there is some indication that the incidence of Alzheimer’s is decreasing, the Alzheimer’s Association projects that 14 million people in the US will be affected by 2050. At the same time, deaths from cancer and other diseases are on the decline.
Neurofibrillary Tangles May Be The Real Culprit
Although the lion’s share of research dollars has gone to searching for a way to clear beta amyloid from the brain, some recent studies focus on Alzheimer’s tangles. In fact, it seems that tangles do more damage than plaques. Given that drug trials aimed at eliminating amyloid plaques have failed repeatedly, addressing the other half of the protein duo will hopefully be more successful.
Researchers in California and the Netherlands think they might have found a way to control the formation of neurofibrillary tangles by modifying cholesterol metabolism in the brain.
In the online issue of Cell Stem Cell published January 24, 2019, the team reported a potential “druggable target” that may help influence the production of the tangles as well as plaque. The target: cholesteryl esters (CE), which store excess cholesterol. These CEs also serve to regulate tau, the protein that mutates to form tangles.
By testing a battery of FDA-approved drugs, the researchers found that efavirenz (a drug used to combat HIV) lowered CE, which in turn reduced tau in neurons. The hope is that lowering levels of tau will reduce tangle buildup and provide a viable treatment against the progression of Alzheimer’s.
Though promising, this research is very preliminary. On the other hand, it represents a new direction. Hopefully, concentrating on the role tangles play in Alzheimer’s disease will prove more fruitful. Or perhaps, progress will be made when we better understand the connection between the hallmark plaques and tangles.
Our immune system and Alzheimer’s — if tau is the problem what is the solution?
Scientists at Washington University School of Medicine in St. Louis think they found just such a connection. Even though researchers are looking for a way to mitigate beta amyloid from the Alzheimer’s brain, we know that these plaques can be present without causing cognitive decline. The tau tangles are the real culprit. It is just that plaques open the door to tangles.
In other words, the presence of Aβ plaques makes the development of neurofibrillary tangles more likely, and it is the tangles that precipitate Alzheimer’s pathology.
Now, according to the Washington University study, published in the journal Nature Neuroscience on June 24, 2019, there is a stronger connection between plaques and tangles than previously thought. The link seems to involve microglia in the brain. If you follow this blog you know about microglia and the potential they have to resist Alzheimer’s.
Read more about microglia and how energizing microglia helps Alzheimer’s on our blog:
Microglia are little garbage collectors. They are small particles in the brain that remove pathogens like viruses, and keep the brain free of dead cells and debris. Unfortunately, these little cleaners seem to become less active when Alzheimer’s disease is present. We have reported on a couple of procedures that inspire microglia to be more active. Both have been tested with human subjects and have produced improvements to Alzheimer’s pathology, including better memory and cognitive functioning.
David Holtzman, head of the Department of Neurology at WU and senior author of the study thinks that, “If you could break that link in people who have amyloid deposition but are still cognitively healthy, you might be able to stop disease progression before people develop problems with thinking and memory.”
Dr. Holtzman thinks that interfering with tau tangles predisposition to gather around brain plaques will somehow involve the brain’s immune system. There is a mutation in the TREM2 gene that weakens microglia. A group of lab mice with this mutation developed more tau tangles than did mice without it. Furthermore, the tangles were concentrated around the amyloid plaques. He hopes drugs that influence the microglia will break the link between plaques and tangles. If plaque buildup is caught early enough, such treatment could stop the progression of the disease.
This research is exciting, as is the other research involving microglia we are following. I am a little concerned that these researchers are always hoping a drug will be found to solve the problem, or mitigate the condition. Flashing light offers a way to stimulate microglia to action. So does targeted ultrasound. Both of these non-invasive procedures work to entice the immune system to keep the brain clear of protein gone bad. And even though the scientists that are working with flashing light therapy and targeted ultrasound are also thinking that a drug will make for even better results, we can hopefully get the effect we need without drugs.
A mouse with human immune cells will help study immune response to Alzheimer’s
The Chimera of Ancient Greek Mythology
As Alzheimer’s research turns away from its fixation on amyloid plaques, more energy is being directed at microglia. What role might the human immune system have in controlling this dreaded disease?
Although investigators see some remarkable results in human subjects using microglia-stimulating procedures (e.g., flashing light and ultrasound stimulation), they can’t see what is actually happening in the living human brain.
For obvious ethical reasons, these observations are only possible post-mortem. Because of this, scientists rely on animal studies. The problem with animal studies, as readers of this blog know, is that the results do not always relate to human conditions. Animal brains are not exactly the same as human brains. This fact is particularly relevant in this case, as mouse microglia behave very differently than do human microglia.
Enter the chimeric mouse. The word chimeric is derived from the Greek Chimera. The Chimera is a beast of Greek mythology that Homer described as “lion-fronted and snake behind, a goat in the middle.” That is, a creature containing parts of more than one animal. A hybrid.
Behold the Chimeric Mouse – part mouse and part human
A research team at the University of California, Irvine, have created a modern day Chimera, part mouse and part human. Well, mostly mouse. The human part is tiny microglia in the mouse’s brain. The UC Irvine scientists managed to grow human microglia in mice by “seeding” the mouse brain with pluripotent stem cells. These special stem cells were created from cells from adult human volunteers. They have the ability to create almost any type of cell.
It is more complicated than that, but in a few months and with a little coaxing, 80% of the microglia in the brains of the test mice were human microglia. Because of this breakthrough, scientists are now able to watch human microglia in action ー in real time! This should prove to be a major advance in the study of the Alzheimer’s brain.
When scientists at UC Irvine introduced amyloid into the Chimera’s brain, they observed the human microglia gathering around these destructive proteins. Meanwhile, the mouse microglia did not respond to the plaques.
Moreover, the observations agree with the inferences made by researchers in earlier human studies; that microglia and the human immune system are indeed something to add to our list of potential weapons in our fight against Alzheimer’s.
And we now have a powerful tool to help develop that weapon: Chimera.
One more observation, if I may. Despite the remarkable results that inciting microglia to action have on Alzheimer’s pathology, effects seem to be short-lived. That is, without continued treatment, symptoms return. It seems to me, then, that these therapies treat a symptom rather than the cause.
This is not to say that removing a symptom is not progress. I, personally, look forward to the day that we can eradicate Alzheimer’s disease, as well as other dementia, without relying on regular treatment–especially drug treatment. That will be a cure.
Organizations & Affiliations
Purple Angel Ambassador
Dementia Friendly America
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