The Brain Plaques and Tangles That Cause Alzheimer’s

The Brain Plaques and Tangles That Cause Alzheimer’s

Meryl Comer: The mainstream research has been focused on beta amyloid.  Tau has always been there, but now there is a big controversy about where the progression comes, where does it really lie?  Take that debate on Dr. Gandy. 

Dr. Gandy:  Well certainly people with Alzheimer’s disease have two sorts of lesions in their brains, two sorts of clumps of protein.  Some of these clumps are in between nerve cells, and others are inside nerve cells.  The ones that are in between the nerve cells are called amyloid plaques.  The clumps that are inside the nerve cells, which are twisted, are called tangles or neurofibrillary tangles.  Now for many years we didn’t sort of know what the sequence of events was, but it is very clear now that all the genes that cause Alzheimer’s disease point to the buildup of amyloid. So it appears that Alzheimer’s disease amyloid comes first and tangles come next.  They may be extremely important in understanding why the nerve cell dies.  Now the disease that Dr. Troncoso mentioned, frontal temporal dementia, has also helped us to understand the relationship between plaques and tangles because in that disease the mutations that cause the genetic forms are in the protein called tau that builds up and causes tangles.  People with frontal temporal dementia get tangles, but they never get plaques, so in Alzheimer’s disease plagues can cause tangles, but in frontal temporal dementia tangles don’t cause plaques.

Meryl Comer: Well why is it so hard these days to get a grant from NIA around beta amyloid when you can get it for tau?

Dr. Gandy:  Well so there is a specific reason for that that’s really evolved a lot in the last year.  There is a study that was reported this spring that showed using an antibody, a chemical aimed at the amyloid substance... that if people with mild Alzheimer’s disease received antibody infusions, anti-amyloid infusions, for a year and a half that the amyloid buildup in their brains would go down by about 25%.  They didn’t change at all clinically.  They didn’t get any better in terms of their cognitive function.  Why is that? Because we didn’t start early enough, because we didn’t treat long enough or because it’s actually another form of amyloid, not the plaques, but these floating clumps called oligomers?

Meryl Comer:  You wanted to make a point, yes, doctor. 

Dr. Troncoso:  Yeah well, I think that there is a lot of debate between the amyloid and tau deposition, but I think one should not get stopped at that point of that argument because it’s perfectly possible that one of these abnormalities, let’s say amyloid may trigger the rest and there is more than amyloid and tau.  We haven’t spoken, but there is a very significant inflammatory, inflammation in the brain that once you have perhaps amyloid and tau trigger that event it becomes self-sufficient.  It actually may even promote more amyloid or more tau deposition, so I think that tau it may be as important as amyloid, but it may be later on in this progression of the disease. And if you could actually target each of these elements it probably would be beneficial. So I don’t see really a tremendous dichotomy, antagonism between looking at amyloid and tau.  I think that both are perfectly legitimate targets of research and one more perhaps disgression in terms of the dementia that is being seen in patients who have head trauma.  Most of that, the lesions that they have is of the tau type, so I think both of these targets amyloid and tau should be addressed.  There is no reason to eliminate one of them.

Dr. Gandy:  There is the one experiment to mention that might also explain why the shift sort of toward tau.  A lot of what we’ve learned about Alzheimer’s disease is from mouse models.  Mice normally never ever get Alzheimer’s disease because their amyloid is different enough that it doesn’t clump and build up.  If we then put into a mouse the gene for amyloid and with a mutation that would cause it to build up and the gene for tau so that it will get tangles, then as that animal ages it will get buildup of plaques and tangles just like, similar to humans with Alzheimer’s disease.  They will then lose their ability to find their way around their cage or to find their way around a swim maze.  If you then treat them with a drug or substance that will decrease the levels of tau, will lower the tau down, the cognitive function comes back, so it’s possible to sort of render the amyloid inert if you can turn down the tau at least in the mouse model.

Amyloid plaques and neurofibrillary tangles inside the brain are the best explanation we have for how Alzheimer’s develops.

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Yale scientists restore brain function to 32 clinically dead pigs

Researchers hope the technology will further our understanding of the brain, but lawmakers may not be ready for the ethical challenges.

Still from John Stephenson's 1999 rendition of Animal Farm.
Surprising Science
  • Researchers at the Yale School of Medicine successfully restored some functions to pig brains that had been dead for hours.
  • They hope the technology will advance our understanding of the brain, potentially developing new treatments for debilitating diseases and disorders.
  • The research raises many ethical questions and puts to the test our current understanding of death.

The image of an undead brain coming back to live again is the stuff of science fiction. Not just any science fiction, specifically B-grade sci fi. What instantly springs to mind is the black-and-white horrors of films like Fiend Without a Face. Bad acting. Plastic monstrosities. Visible strings. And a spinal cord that, for some reason, is also a tentacle?

But like any good science fiction, it's only a matter of time before some manner of it seeps into our reality. This week's Nature published the findings of researchers who managed to restore function to pigs' brains that were clinically dead. At least, what we once thought of as dead.

What's dead may never die, it seems

The researchers did not hail from House Greyjoy — "What is dead may never die" — but came largely from the Yale School of Medicine. They connected 32 pig brains to a system called BrainEx. BrainEx is an artificial perfusion system — that is, a system that takes over the functions normally regulated by the organ. The pigs had been killed four hours earlier at a U.S. Department of Agriculture slaughterhouse; their brains completely removed from the skulls.

BrainEx pumped an experiment solution into the brain that essentially mimic blood flow. It brought oxygen and nutrients to the tissues, giving brain cells the resources to begin many normal functions. The cells began consuming and metabolizing sugars. The brains' immune systems kicked in. Neuron samples could carry an electrical signal. Some brain cells even responded to drugs.

The researchers have managed to keep some brains alive for up to 36 hours, and currently do not know if BrainEx can have sustained the brains longer. "It is conceivable we are just preventing the inevitable, and the brain won't be able to recover," said Nenad Sestan, Yale neuroscientist and the lead researcher.

As a control, other brains received either a fake solution or no solution at all. None revived brain activity and deteriorated as normal.

The researchers hope the technology can enhance our ability to study the brain and its cellular functions. One of the main avenues of such studies would be brain disorders and diseases. This could point the way to developing new of treatments for the likes of brain injuries, Alzheimer's, Huntington's, and neurodegenerative conditions.

"This is an extraordinary and very promising breakthrough for neuroscience. It immediately offers a much better model for studying the human brain, which is extraordinarily important, given the vast amount of human suffering from diseases of the mind [and] brain," Nita Farahany, the bioethicists at the Duke University School of Law who wrote the study's commentary, told National Geographic.

An ethical gray matter

Before anyone gets an Island of Dr. Moreau vibe, it's worth noting that the brains did not approach neural activity anywhere near consciousness.

The BrainEx solution contained chemicals that prevented neurons from firing. To be extra cautious, the researchers also monitored the brains for any such activity and were prepared to administer an anesthetic should they have seen signs of consciousness.

Even so, the research signals a massive debate to come regarding medical ethics and our definition of death.

Most countries define death, clinically speaking, as the irreversible loss of brain or circulatory function. This definition was already at odds with some folk- and value-centric understandings, but where do we go if it becomes possible to reverse clinical death with artificial perfusion?

"This is wild," Jonathan Moreno, a bioethicist at the University of Pennsylvania, told the New York Times. "If ever there was an issue that merited big public deliberation on the ethics of science and medicine, this is one."

One possible consequence involves organ donations. Some European countries require emergency responders to use a process that preserves organs when they cannot resuscitate a person. They continue to pump blood throughout the body, but use a "thoracic aortic occlusion balloon" to prevent that blood from reaching the brain.

The system is already controversial because it raises concerns about what caused the patient's death. But what happens when brain death becomes readily reversible? Stuart Younger, a bioethicist at Case Western Reserve University, told Nature that if BrainEx were to become widely available, it could shrink the pool of eligible donors.

"There's a potential conflict here between the interests of potential donors — who might not even be donors — and people who are waiting for organs," he said.

It will be a while before such experiments go anywhere near human subjects. A more immediate ethical question relates to how such experiments harm animal subjects.

Ethical review boards evaluate research protocols and can reject any that causes undue pain, suffering, or distress. Since dead animals feel no pain, suffer no trauma, they are typically approved as subjects. But how do such boards make a judgement regarding the suffering of a "cellularly active" brain? The distress of a partially alive brain?

The dilemma is unprecedented.

Setting new boundaries

Another science fiction story that comes to mind when discussing this story is, of course, Frankenstein. As Farahany told National Geographic: "It is definitely has [sic] a good science-fiction element to it, and it is restoring cellular function where we previously thought impossible. But to have Frankenstein, you need some degree of consciousness, some 'there' there. [The researchers] did not recover any form of consciousness in this study, and it is still unclear if we ever could. But we are one step closer to that possibility."

She's right. The researchers undertook their research for the betterment of humanity, and we may one day reap some unimaginable medical benefits from it. The ethical questions, however, remain as unsettling as the stories they remind us of.

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