Search for tag: "synapses"

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.

Interviewer: Alzheimer's, autism, fragile X syndrome, and memory loss all have something in common. There's a protein in the cell called Arc, which is thought to be an important part in causing all of these syndromes. My guest, Jason Shepherd, an assistant professor in neurobiology and anatomy, is investigating this protein and what it can tell us about how the brain works. Dr. Shepherd, what is it that all of these diseases have in common?

Dr. Shepherd: Well, we think that the way information is stored in the brain is through the way the cells in the brain connect to each other, and those connections are called synapses. A lot of what we're studying is how those synapses work, how they change when you experience something. This protein, Arc, we think is critical for transducing information from the outside, so changing anything you experience or something that you're learning into molecular changes at those synapses in the brain.

Interviewer: So it has to do with memories or learning or both?

Dr. Shepherd: Both. Memories are just learning that's been stored for a certain amount of time. Really, that's the main question my lab is trying to answer: at the cellular molecular level, how is information stored in the brain for the long term? This is really critical for what the brain does.

Interviewer: I can kind of understand how that might work with, say, memory loss and Alzheimer's. But how would that figure in to something like autism?

Dr. Shepherd: The brain evolved to store information and use that information to modulate behavior. The [inaudible 00:01:47] of behaviors that go wrong in autism are very complicated behaviors like social interaction and language acquisition. We think that because this gene is so critical for maintaining those synaptic changes, any way that you can have a deficiency in that gene or it's misregulated, you get cognitive dysfunction.

Interviewer: And an Arc could be a way that the organism, the animal or the person, is processing their environment and learning from their environment.

Dr. Shepherd: Yes. Arc is one of those genes that's really tightly regulated by experience. In a normal brain, if you're just sitting in a room, not learning thing, its expression is very low. As soon as you start to learn something or you experience something novel, the gene gets turned on and the protein itself is highly regulated at the synapse. So it's downstream of all these signaling events in the cell.
The cell really just wants it to be on and off very quickly. A lot of these diseases seem to result from other mutations or something going wrong in one of those signaling events and because Arc is the protein that seems to be doing a lot of the work at the synapse, we think that it's involved in a lot of these diseases because it's sort of the endpoint of those signaling cascades.

Interviewer: What are you investigating?

Dr. Shepherd: Well, right now we're sort of taking a very multi-pronged approach, so everything from trying to figure out what the structure of the protein is, what it's doing at the synapse, all the way to how it affects circuits in the brain. So we have a microscope that allows us to image into a mouse even while it's awake and behaving so we can image the activity of the neurons and how they change during a learning experience.
Then we can see how Arc has changed during that experience. If we manipulate the protein level, what happens to the way the animal learns. We can do that both in a normal mouse as well as in mice that we model those autism spectrum disorders or Alzheimer's or even schizophrenia.
There was a recent study that came out looking at human patients, and one of the exciting things in psychiatric disorders is that we can now sequence genomes of people and find out what are the genetic inheritants, or what are the genes involved in some of these diseases.
One of the sets of genes that have come out are the ones that seem to act at the synapse, and Arc is one of those as well. So we think that there's really tight links between these psychiatric disorders and I think the big issue now is trying to figure out why some are causing schizophrenia, why some are causing bipolar, why some are causing autism. Even within the same family that has similar mutations, you can get all three of those psychiatric disorders.

Interviewer: I mean, we know that these disorders run in families, but yet, sometimes it's not a single disorder. So you think this might be a link?

Dr. Shepherd: Yeah. Because I think the whole question of nature versus nurture is not really a question anymore. It's clearly an interaction of both. So this gene is one of those genes that is in the middle. It's a gene that's regulated by genetics because it's regulated by a bunch of other proteins that are involved in those signaling cascades, but then it's also responsive to the environment so that whatever is happening to the brain and that circuit, that's acting in response to what the organism is doing at any given time.
We know that, obviously, experiences and the environment affect a lot of these psychiatric disorders and when they manifest. So we think that, yes, there could be a link between the two.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.

Interviewer: Alzheimer's 101. What is it? What's happening in the brain? What are some of the symptoms? What can be done, and what's on the horizon for potential cures. We're with Dr. Norman Foster, Director of the Center for Alzheimer Care, Imaging, and Research at the University of Utah.

First of all, let's talk about what is Alzheimer's? What are the characteristics of Alzheimer's, and what's actually happening in the brain? I find that kind of interesting.

Dr. Foster: Alzheimer's disease is a progressive disease of the brain that causes loss of nerve cells, and as a result patients first develop difficulty with memory. But then increasingly over time have difficulty with other areas of thinking and then eventually difficulty with daily activities so that they become dependent on others.

Interviewer: When you say nerve cells, is it brains cells?

Dr. Foster: These are brain cells. Yes, that's right.

Interviewer: These are brain cells. And what exactly is happening in the brain? I've heard it described as plaque of the brain. Is that accurate or not?

Dr. Foster: Well, Alzheimer's disease is caused by an abnormal accumulation of two proteins that normally occur in the brain, but in this disease abnormally aggregate into plaques and into tangles. And we now understand a lot of the basic biology of these uncontrolled protein accumulations. But we don't understand what sets this process off.

Interviewer: So these proteins start accumulating in the brain. Do they actually adhere to brain cells?

Dr. Foster: Not directly. They adhere to each other. So they begin with small fragments of protein, and then they aggregate into clumps. And then eventually form these plaques, or in the case of the tau protein, which makes the neurofibrillary tangle. These fibrils actually kind of have a spun or twisting appearance and interfere with normal nerve function.

Interviewer: It's kind of gumming up the works.

Dr. Foster: That's right. This is a disease that as far as we know just involves the brain.

Interviewer: So you spoke earlier about the symptoms. What are some things that if I'm a relative of somebody that I believe might be getting Alzheimer's I would want to be looking about for?

Dr. Foster: Well, the characteristic feature that late in life, on average in the mid-70s, people begin to have difficulty with memory. And, of course, we all have memory complaints.

Interviewer: Yeah.

Dr. Foster: And our memories are not perfect. We don't work like computers, but in these cases it interferes with a person's ability to do daily activities that they've been used to carrying out independently.

Interviewer: So, for example, perhaps they forget where they are when they're driving someplace where they've driven to numerous times.

Dr. Foster: That's possible. This is why medical attention, medical advice is so important because there's some things that are obvious, but we think it's very important to pick these up when things are not so obvious. And so there may need to be medical judgment.

One of the examples that I would use having trouble remembering exactly where I parked in a large shopping mall. That's normal, but after four or five hours not being able to figure out where it is or how to get help, that's abnormal.

Interviewer: Or how to get help. That's an interesting addition as well. When speaking of Alzheimer's, what can be done if you go and you talk to a physician to help you find some of those non-subtle things, your family member has been diagnosed with Alzheimer's, what then?

Dr. Foster: Well, I think the first important step is to know what is going on. It's quite a step. In fact, there's quite a bit of effort to evaluate what the cause of memory problems and cognitive problems are.

Interviewer: It could be something other than Alzheimer's.

Dr. Foster: It could be something other than Alzheimer's. It could be Alzheimer's with something else. For example, sleeping medications are common. Even over the counter sleeping medications can make Alzheimer's disease significantly worse, or it can cause symptoms that mimic Alzheimer's disease.

So first, making sure you know what you're dealing with is important. And then that, of course, will lead to what should be done about it.

Interviewer: Okay.

Dr. Foster: So there are many things that can be done about Alzheimer's disease where medications that are approved by the Food and Drug Administration that we know have benefits. Unfortunately, they're only modest right now, so we're looking for much more effective drug treatments.

Interviewer: Does that slow down the onset of Alzheimer's'? Does it get some memory back? What do these drugs do?

Dr. Foster: Well, the medications that have currently been approved by the F.D.A. compensate for chemical losses that occur in the brain typically in Alzheimer's disease. So many of them are very specific for Alzheimer's disease, and don't affect or improve all kinds of memory and thinking problems. But this is actually the kind of chemical byproducts of the plaques and tangles rather than getting at the plaques and tangles themselves.

Interviewer: What do those chemical byproducts do?

Dr. Foster: Our nerve brain cells talk to each other by what are called synapses. So there's a chemical that's released at the end of one nerve that is then picked up by another nerve. And so when nerves are sick, they have difficulty synthesizing, creating this chemical message system, and that's what these drugs do is try to compensate for that, restore some of the chemical changes that are lost in Alzheimer's.

Interviewer: What else can be done? So you've got some medications. What are some other options?

Dr. Foster: Right. So right now one of the important things to do is help the patient. The patient needs to have help with day-to-day activities or doing things. For, example, if it's only memory problems, then one of the things you need to do is write down things so that you can read and to see what you remember.

We can no longer do or depend upon some things that we took for granted before. So, for example, you're in the doctor's office. The doctor says, "Come back and see me in two weeks," and they give you a date. And then after the doctor leaves the office if they haven't written it down, you don't remember that day.

Interviewer: Yeah.

Dr. Foster: Now, maybe that could happen with any of us, and it's always a good idea to write those down or keep a calendar. But if you know that you have Alzheimer's disease or a memory problem, that's something that you really have to pay a lot of attention to. But there are other things that are very predictable. Complications, I call them, of Alzheimer's disease that need to be addressed.
Other Effects of Alzheimer's

For example, people who have memory problems get embarrassed by this, and so we often see that patients and often other family members become socially isolated. That's exactly opposite of what people with this disease need. They need to be interacting with others, have a good quality of life. And not leaving your house, and sometimes the wife or husband not leaving the house also, that's bad.

Another example is social activities. You may be embarrassed because of memory problems and withdraw from your friends at the very time that there's most important to you. And then also there can be problems with family. A family doesn't understand what's going on. They misunderstand and, therefore, act on assumptions that they make that are in error, particularly if they haven't sought medical advice to understand what's going on.

So one daughter might think, "Well, he's just trying to get back at me. That's why he's not doing things." Or "I think he's just depressed so we should try to make him happy." Or that this is related to medication. There are all sorts of possible explanations, but the family members are pulled apart by disagreements and conflicts, not being on the same page about how to support their loved one. Then we often see disasters, complications not just socially but within families because of this disease.

Interviewer: It appears as though the Alzheimer's affects the brain. Does it otherwise affect you physically directly, or is it the indirect effects? You're embarrassed. You don't leave the house. So now you're not getting any exercise. You're not getting any social interaction. Is that where a lot more of the danger is?

Dr. Foster: Well, I often get asked questions about whether Alzheimer's disease kills? And we know the people who have Alzheimer's disease at every point in their illness are at greater risk of death. Now, this doesn't just happen because of the plaques and tangles, but because we depend on our brain for many things.

Interviewer: Yeah.

Dr. Foster: You just described some of them. Our motivation, for example, get up and go, all of that sort of thing makes a big difference in our physical health. We know that people should be active, but also it affects our ability to seek help. For example, if you have chest pain and you're not able to seek help, then you're going to die from a heart attack more likely than somebody who does seek help.

If you forget the medication that you need to take for diabetes, then you're going to have complications of diabetes and die from that earlier. Our brain also-in ways that we don't as much understand-are involved with basic daily function and maintaining our physical health. So that people who have brain injuries, whether it's due to trauma or other things die earlier than people who have good functioning brains.

Interviewer: Let's talk about some potential cures or things on the horizon that excite you. I know that you keep very in touch with the research that's going on in the United States and the world. Is there hope on the horizon?

Dr. Foster: There is hope. We know much more about Alzheimer's disease. And I think one of the important things to recognize is that Alzheimer's isn't simple. It's a complicated disease. There are two proteins that accumulate. They affect the brain in complex ways. They change the chemistry of the brain.

So I think that it's unrealistic to expect that we're going to find a single drug or penicillin that's going to cure the disease. It's much more similar to cancer. We're going to make gradual, progressive improvements step-by-step, identifying how this disease develops and stopping it in its tracks.

And, of course, a lot of our efforts now are in trying to develop treatments that we would give early in the disease before there's so much damage to the brain. So we think that it's much more difficult after there is so much damage to the brain of correcting the problem. So early identification, early treatment is the way we're going, and there are many exciting possibilities.

We know that these two proteins that accumulate in the brain do so when they get slightly off balance earlier in life. So these slight differences or the slight imbalance over a period of years becomes devastating to the brain. And if we can offset even in a little way this imbalance, then we'll be a long way to brain health.

In addition, we know that the brain is not static. The brain can change. The brain, we call this plastic. It responds to differences in the environment, and there's good evidence now that some older individuals have resistant brains to these effect. And the resiliency is one of the things that we're trying to capitalize on, understand why some patients are so devastated by the same changes that can have less effect in others.

It's time for us to give the best care to patients with Alzheimer's disease. They deserve the dignity and dignity of care.

updated: December 2, 2020
originally published: September 25, 2013