Where blood flow meets brain diseases

Certain diseases like Alzheimer’s and high blood pressure are known to alter the link between brain activity and blood flow changes in the brain, leading to improper blood flow delivery to brain cells. This eventually leads to the death of brain cells and cognitive decline. Dr. Paulo Pires, assistant professor of physiology and surgery and BIO5 member, studies how blood flow to the brain changes between healthy and disease states, with an eye on possible therapies that can improve blood flow to mitigate disease.

Tell us a bit about blood and the brain - why is getting an adequate amount of blood to the brain so important, and how does it affect different diseases like Alzheimer’s? 

The brain is very interesting in that aspect because it's a very highly active organ. It requires a lot of energy in order to operate - everything that we do is somewhat controlled by our brain. One of the paradoxes of the brain is that even though it requires so much energy, it doesn't store anything. 

For example, if you think about when you go exercise, even most people like me can usually wake up, drink coffee, and go exercise. Our body can run on the storage of glucose in our muscles. The brain doesn't have that, so everything that the brain cells need have to be delivered in real time. 

When you have an increase in activity, for example, right now if you're listening to me and paying attention, certain areas of your brain are processing all of this information. Those cells, if they were quiet before, now they're active. They need more energy in order to operate, and that energy needs to be delivered in real time by the blood.

Whenever we see that increase in activity, there is a matching blood flow response. This has been known for a long time - the first studies came out in the late 1800s in England - but it's only been in the last 30-40 years that, with advances in imaging, we’re actually able to understand how this process is controlled. 

Now that we have a better understanding of how it's controlled, we're also trying to understand why it is not working properly in some diseases. One of them are diseases that are linked to dementia, for example, Alzheimer's. One of the things that we know in Alzheimer's disease is that there is an impaired blood flow response.

Now, who comes first: chicken or the egg? That's the question from my laboratory, and we approach this from a very vascular-centric way. We think that what's happening in those diseases that lead to dementia is that you have an impairment in the delivery first, so your delivery doesn't work as properly. Because it doesn't work as properly, your brain cells are not receiving as much nutrients as they need and over time they die, so we start to have neurodegeneration.

Essentially, we think that we're going to start seeing those vascular changes first that will then lead to neurodegeneration, in part. 

You mentioned you think something that contributes to neurodegenerative diseases is impaired blood delivery, so do you know or are you working towards understanding what causes that blood delivery to decrease?

We know some, but the whole picture we still don't understand.

One of the things that we know is that the blood vessels in our body have many different layers of different types of cells, and one of those types of cells are called the endothelial cells. Those are the cells that are on the inside of the blood vessels, so they're lining the inside of the blood vessels and they are in direct contact with the blood. What we know is that these cells are extremely important for understanding the environment and mounting a response that will lead to an increase in blood flow to certain areas that are active.

In Alzheimer’s disease, for example, as well as hypertension, obesity, and diabetes, to some extent change the function of these endothelial cells so that they are no longer able to mount a very robust response to cause an increase in the diameter of those vessels to allow more blood to flush in on those areas that are needed. 

Another thing that we know happens, and this is very particular for Alzheimer’s disease, is that one of the misfolded proteins, or one of the culprits of Alzheimer’s disease, actually causes death of other cell types in the vasculature which are the ones that are responsible for changing the vessel diameter and are communicating with the endothelial cells.

When they die, then you lose that ability to increase your diameter and then the misfolded protein forms a scar in the vessel wall. It’s like replacing a rubber band with a band of steel. That ability that your vessels have to increase the diameter or decrease the diameter to adjust the needs of that particular area of the brain is lost because now you have a rigid pipe that cannot move.

There are other things we know that alter communications of brain cells, but most of the studies really are focused on endothelial cells, because those are the ones, at least in our laboratory, that are the focus that we can use as a target and maybe reduce or at least slow down the progression of neurodegeneration.

You mentioned Alzheimer’s and dementia – are there other diseases that are included in your work? 

Yes, one of them comes from my PhD training at Michigan State University where I worked a lot with ischemic strokes.

Ischemic stroke is a vascular event - there is no more vascular disease in the brain than an ischemic stroke. We're looking at different targets (proteins) that we may be able to access to potentially make the infarct or the loss of brain tissue smaller, with the ultimate goal to improve recovery or reduce the loss of motor coordination.

We now have a new model to study where we cause a much more focused stroke, activate a drug with light, and can choose where in the brain we can cause that damage, and by changing the size of the light that we're adding we can make this stroke bigger or smaller. We can look at different aspects and how different areas of the brain may be responding differently. 

We also have plans of looking at other diseases such as Parkinson’s or Huntington's where the evidence for a vascular impairment is not as strong as it is for Alzheimer’s, but it's still there, so we're slowly trying to expand our portfolio and see what is happening with the vasculature in all of these different kinds of situations.

One of the things that is interesting about blood vessels is that there's a lot of redundancy in the system, so you have many different pathways that will culminate in the same response. 

How did you get into this line of work?

When I came to the United States in 2007, and I had finished my master's degree back in Brazil, 

I was working in cancer research at the time. I came with my wife who got a PhD position at Michigan State University. I applied to a position at Michigan State University for lab technician, and as it turns out, the boss was working in cerebral circulation. It was completely different from what I was working on before - I didn't really understand the brain and how the vessels in the brain were so different. 

Even though I didn’t know about the brain vasculature, I had experience with some techniques that she wanted in her lab so she hired me, and we got along really well. I absolutely fell in love with the field and I’ve never left. 

When I went into my postdoc at the University of Nevada Reno, that really cemented my love for the vascular. I went from looking at what happens during a stroke to the nitty gritty of how the vasculature works, and from that experience, I knew this is what I wanted to do.

Just to differentiate myself from my previous training, I decided to go more towards neurodegeneration, but those two experiences were really what cemented my love in this area.

Talk to us about your experience serving as a mentor to others.

I have a postdoc, a few graduate students, and a couple of undergrad students. I mentor them as much as I can - because I had great mentors, I just want to pass that along.

Mentorship was one of the driving forces for me to go down the academic scientific path. Nowadays, the private sector has so many opportunities for really good science, but at least from my understanding, you don't get the same type of close mentorship that you get in academia where you're training someone to be a scientist, and you watch them grow and develop. It's unique and it's beautiful.

How does your work help to inform potential therapies for diseases that might be in the brain and affected by blood flow?

The way that I think about this is finding the common problem. What is one thing that all of these pathways are going to merge into where they're stopping? That's where they are impaired, so if we find common targets among different types of diseases, then we have something that we can treat and our research can have a broader application.

One problem with the brain circulation is that it's very unique from the rest of the body, which is good and bad. 

It's good because it gives us a better opportunity for more specialized therapies. It's bad because it's kind of difficult to formulate your hypothesis based on a rationale that you get from the literature, so we always have to do a little bit more groundwork.

The goal is that we find this funnel where everything is stopping and see if it’s something that’s unique enough that we can intervene in a specific way without affecting the entire physiology of the body. We need to find what is unique about the cerebral circulation and if we can target it, because another problem is getting drugs into the brain.

The way that my lab is trying to go about this is using gene therapy. A group in Germany studying Alzheimer’s actually found one type of virus that is fairly specific for individual cells in the blood vessels in the brain, so we can use that tool (virus) to add to or remove things from the endothelial cells in a specific, targeted way. If we can do that, maybe we can pass it on to a therapy.

We often talk on the podcast about finding work-life balance with a demanding job like yours, so what are some of the things you do outside of work that help you recharge?

I'll tell you the things we used to love to do before we had a newborn, because now we are focused on sleeping whenever we can. 

One of the things we love about Tucson is all the opportunities to hike. You can go 10-20 minutes in any direction and find yourself in the middle of the wilderness. We live near Sabino Canyon, so that was our weekend morning activity. We hope to get back to doing that soon once the kid is a little bigger. We are also foodies, so we like to go to restaurants and try all of the outstanding food in Tucson.

We think of our researchers as superheroes, so if you were a superhero, what do you think your superpower would be?

If you asked my students, super-nagging would be my superpower, and theirs would be the ability to block me out!

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