To this day, Sidney Strickland, PhD, the Zachary and Elizabeth M. Fisher Professor in Alzheimer’s and Degenerative Disease at The Rockefeller University, abides by a simple but uncompromising work ethic: “Dig one well deep.”
Dr. Strickland has spent decades unraveling connections between blood flow, inflammation, and neurodegeneration. His work focuses on the circulatory system as a potential root cause of Alzheimer’s—paving the way to therapeutic approaches that could revolutionize how we treat and even prevent the disease.
In this conversation, Dr. Strickland reflects on his journey from Memphis to neuroscience, the pivotal moments that shaped his path as a researcher, and his vision for therapies that could not only slow Alzheimer’s progression but even restore lost cognitive function.
MUSIC AND NUCLEOTIDES
What put you on a path to becoming a scientist?
I grew up in Memphis, Tennessee—a very long way from New York City—where I came under two influences that changed my life. One was music, i.e., Elvis—I’m still an avid guitar player when I’m not in the lab. The other was my sister, who studied biology and had a real knack for explaining difficult concepts without oversimplifying them. She opened my eyes to the wonders of science—all the possibilities that await just beyond the difficult language and the technical intricacies.
One day, when I was fifteen, my sister came home from college and described an experiment that completely blew me away. It was this beautiful study that proved how the information encoded in DNA is read in groups of three. Basically, researchers removed sequences of one, two, and three nucleotides and found that only in the latter case DNA continued to function, indicating that three was its fundamental structural unit. Such a consequential discovery, and yet so simple—I was enamored! At that moment I knew I wanted to be a scientist.
How did you end up becoming a biochemist?
It was thanks to people who really helped me identify where I could do my best work. I went to Rhodes College for my bachelor’s degree, and initially I was considering majoring in mathematics. I did well, but I felt that advanced math courses became a little too abstract for my taste. I told one of my professors, and he switched the light on for me: “You like applied mathematics—you should go into a field where mathematics is used as a tool.”
From there I discovered biochemistry, which back then was really just emerging as a field. Kids now learn about it in ninth grade, but at the time it was so cutting-edge there was no class I could take. I mentioned this to another professor, and he made an incredible offer: “Let’s do a tutorial. You find a good book, and we’ll read it together.” So that’s what we did—I found a textbook, and for an entire semester we read chapters and met to discuss them. And that’s how I ended up getting a PhD in biochemistry.
FROM BIOCHEMISTRY TO ALZHEIMER’S
What led you from biochemistry to neuroscience?
It was an interesting sequence of events. My graduate research was mathematical and physics-oriented, which I loved, but also quite niche and arcane. My professor was right—the applicability of my studies has always been very important to me. So, when I first arrived at The Rockefeller University for a postdoc, I knew that I wanted to do something different.
I worked in the lab of the biochemist Edward Reich, and we were studying an enzyme called tPA, which is used to dissolve blood clots. And one day I came across another article that stopped me in my tracks. A group of researchers had been tracking genetic alterations produced by seizures in a part of the brain called hippocampus: and the gene that changed the most, it turned out, was the one that encodes tPA. This was totally unexpected, because tPA is a vascular enzyme, so it wasn’t clear why it would be involved in brain seizures.
Is that when you started to see a connection between blood flow and Alzheimer’s?
Absolutely. The senior author of that article was Eric Kandel, who won the Nobel Prize in 2000 with Paul Greengard. We were friends, so I told him I’d be interested in investigating the role of tPA in brain seizures, and Eric gave me his blessings. Since seizures lead to neurodegeneration, that marked my official entrance into the field.
Because tPA was so heavily involved in seizures, our hypothesis was that it might actually be causing them. To test this, we looked at mice in which the production of tPA had been inhibited—and we found that they were very resistant to neurodegeneration. That was one of the first indications of a direct link between vascular and neurodegenerative processes. And as we tried to understand this better, we came to focus more and more on conditions like Alzheimer’s.
BLOOD CLOTS AND INFLAMMATION
How did that initial finding evolve into your current research agenda?
Over time, our attention shifted from tPA to the broader relationship between the circulatory system and brain inflammation—which we think is a major contributor to Alzheimer’s disease.
In essence, the circulatory system can be affected by major and minor blood clotting, and these correspond to major and minor vascular problems. If you have a thousand minor problems, however, these eventually add up to a major one. So, a minor clot might cause the inflammation of one neuron—which is ok, since there are 86 billion neurons in your brain. But if you let thousands of neurons become inflamed, that eventually is going to take its toll.
Circulatory and inflammatory issues of this kind often start to occur decades before a person develops neurodegenerative symptoms like memory loss. So finding ways to address them could provide new avenues for therapeutic intervention, and potentially even for preventing the onset of conditions like Alzheimer’s.
What kind of therapeutic approaches are you investigating?
We are currently focusing on the contact system, which is a protein cascade involved in blood clotting. This cascade includes a protein called HMWK, which gets cleaved and releases a small bioactive piece that controls fluid flow in and out of blood cells, and so can influence inflammation.
Initially, we wanted to understand at what point of the cascade HMWK gets cleaved, so we developed a monoclonal antibody for diagnostic purposes. But then I started wondering: what if this antibody could actually affect the cleavage process? We tried, and it did—the antibody completely blocks the cleavage of HMWK, and therefore the activation of the contact system. Which means that it also prevents clotting and inflammation downstream.
Does that mean this antibody could potentially be used for treatment?
Yes, it does, also because this approach avoids a lot of problems that could arise from interfering with blood clotting in other ways. For example, physicians might worry that preventing clotting might inhibit blood coagulation, which is an essential process. But that is not really a risk here, because there is a separate chemical pathway that regulates coagulation: so you can block the cleavage of HMWK, and the contact system, without causing side effects like excessive bleeding. You can reduce inflammation without interfering with normal hemostasis.
That means our antibody would be an ideal candidate for combination therapies with anti-amyloid drugs. Take lecanemab, for example, which causes side effects like brain hemorrhage and edema. A lot of these side effects are linked to the activation of the contact system—so, they could potentially be reduced by administering lecanemab together with our antibody. That would pave the way to longer and more vigorous treatment, which would also be more effective.
TERMINAL LUCIDITY
Do you think this kind of treatment could be given at any stage of Alzheimer’s?
I do—and the benefits, in the long term, could be enormous. I used to believe the best we could hope for was maintaining a patient’s condition by preventing disease progression. But now I don’t think that’s necessarily true. Imagine this: a capillary is blocked by a blood clot, so a neuron downstream of that capillary is starved for oxygen, it stops functioning, and your memory begins to fail. But what if by relieving that blood clot, you could reactivate the neuron with all its original connections intact?
This is not science fiction—quite the opposite. There is a phenomenon known as terminal lucidity, where people affected by dementia or some other neurological impairment, at the very end of their life, suddenly come back in a startling way—completely lucid, present to their surroundings, and remembering things they seemed to have lost. This is profound, because it tells you that non-functional doesn’t mean irretrievable. There might be a way to bring people back from neurodegeneration.
Is that what drives you to continue this work?
Yes. In science, every day there is some new branch point—a striking and unexpected finding—and if you follow all of them, you get nowhere. As my mother used to say: “Dig one well deep.”
Once in a while, though, you can start digging somewhere new, and Alzheimer’s for me was one of these opportunities. I loved what I did before, but to me this is much more interesting research because of its potential impact on human suffering. The idea that what we are doing might not only contribute to slowing cognitive decline, but even to restoring brain function—that’s an extraordinary prospect. It keeps me excited about coming to the lab every single day.
