The estrogen frontier in neurodegenerative disease research

In a career spanning decade, renowned scientist Adriana Maggi has been at the forefront of research into the effect of estrogen on the central nervous system.
Bill Hinchberger
Published on 28. Oktober 2021

During that time, science’s understanding of the hormone and its role in preventing neurodegeneration has changed dramatically. Journalist Bill Hinchberger met up with Professor Adriana Maggi at her Italian retreat for an exclusive interview about her groundbreaking work.

The University of Milan recently awarded Adriana Maggi the title of professor emeritus – an honor reflecting an illustrious research career that spanned nearly four decades. Maggi is perhaps best known for groundbreaking studies into the role of the hormone estrogen in possibly protecting against neurodegenerative diseases. She will continue to collaborate with the teams she built through the university’s Center of Excellence on Neurodegenerative Diseases (CEND). Maggi will also continue to play a central role at the University of Milan, notably in the development of its new campus. In addition, she remains vice-chair of the European Union Joint Programme – Neurodegenerative Disease Research (JPND), the world’s largest such initiative in this discipline. We caught up with Maggi at her vacation home in Camogli, a fishing village on the Mediterranean Sea just outside Genoa. In the front yard, on a hillside with a view of the sea, we sat down at Maggi’s makeshift desk, a table more appropriate for a small picnic. Though technically semi-retired and on vacation, she had her computer fired up to work on a scientific paper.
View from Maggi’s vacation home near Genoa.
Asked whether she would be willing to leave Italy to escape retirement and continue to pursue her passion for research, Maggi responded, “How could I leave this?”
<b>Tell us how you got started. <br></b>I got interested in brain function right after receiving my degree [PhD in Biological Sciences, University of Milan]. I started to work on the central nervous system (CNS). I went to Houston [post-doctoral fellowships at the University of Texas Medical School and the Baylor College of Medicine] for five years. I changed totally to focus more on basic biology and cell biology. That was the big thing because hormones regulate transcription. They turn genes on and off. When I came back to Italy, I wanted to work on both the CNS and use the newer background. I started to study how estrogen works with the CNS. At that time, people didn’t think that estrogens could work across the CNS. They thought that they worked only at the basic CNS level to control the cycle and on the periphery. We found that estrogen works in several brain areas. One is the hippocampus, which is important for memory and parental care.
Adriana Maggi on the terrace of her Genoa vacation retreat.

<b>Do you focus only on estrogen or also on other hormones? </b><br>At the beginning I studied others, such as testosterone and progesterone, but I realized that estrogen had a wider effect on the CNS. The CNS is differentiated into male and female very early in development. This is due to estradiol. Testosterone is produced by the gonads of males very early – in humans at the end of the pre-natal period. Testosterone reaches the brain, where it is converted into estradiol. Estradiol makes the brain masculine. To me that was very fascinating; I went on to focus on estrogen.
<b>The idea that there are important differences between males and females today has become very controversial. </b><br>Absolutely. I know. That’s why I liked it.
<b>What have been the biggest advances in your field since you started? </b><br>With estrogen in the CNS, the change has been dramatic. As I said, we felt that estrogens had very limited action in the CNS. We discovered that they do a lot. Probably there is also a neuroprotective effect.
Adriana Maggi being interviewed by Bill Hinchberger.

With regard to neurodegeneration, when I started, we knew virtually nothing. The disorders had been described very well: Alzheimer’s, Parkinson’s, ... We knew where they started in the brain. But about the mechanism, we knew nothing. Partly because we did not have the tools. One dramatic change during my lifetime has been the acquisition of new tools in biology. We have genetics, a tremendously powerful tool – particularly for the CNS, where the system is so complex. We can take cells, stem cells, from a person with a disease and grow them in a culture and study them. This is a big step forward.<br>Another is reverse genetics. Not only can you take the cells from the patient, grow them, study the DNA, and see what is wrong, but you can also take healthy cells from a model organism, change their DNA, and see whether that causes the disease. We never dreamed of this when I graduated. It is extremely powerful. We have tools that we never had before.<br>Molecular imaging is another incredible tool. We can engineer the DNA of cells and then follow a single cell and its metabolism. We used to only see things in dead animals. Now you can study the phenomenon in a live model organism.<br>Thirty years ago, we didn’t know how to tackle the problem. Now we have the tools for a <a href="reductionist approach">reductionist approach</a>, even in vivo.
The reductionist approach is an experimental way to study a complex problem by reducing it to a series of observations. It uses simpler models with fewer parameters in order to construct theories.
<b>Can you talk about a research project of yours that has been particularly significant? </b><br>There are several cell types in the CNS: the neurons, of course, and basically two other cell types – the astrocytes, or astroglia, that help neurons survive, and immune cells that are microglia.
Adriana Maggi researched on the role of estrogen in neurodegenerative diseases.

<p>We discovered that estrogens are anti-inflammatory agents. I looked at the effect of estrogens on microglia. I discovered that estrogens play a strong role in modulating the microglia response to inflammatory stimuli. With an inflammatory stimulus, the microglia become inflamed. They produce products and processes that are important to kill the virus or noxious cells. Or they engulf dead proteins that are toxic to the CNS.<br>Inflamed microglia have to go back to their original status. If they keep producing inflammatory molecules, it is deadly for all CNS cells. When they return to baseline, the cells grow protective agents, growth factors, to repair the damage caused during the inflammatory period. We discovered that estrogens shorten the timeframe of the inflammation. Estrogen induces the cell to have a burst of inflammation, and then go back.<br>This is very important in neurodegeneration because the inflammation in the CNS causes a lot of damage, and probably contributes heavily to neuron death.</p>
<b>Tell me about your involvement with European Union Joint Programme – Neurodegenerative Disease Research (JPND). </b><br>The ministry of research in Italy selected me since I headed the CEND. Each country had to select two people – one from the ministry and a scientist. I was the scientist. I was very enthusiastic about the JPND because I think we were able to establish a nice system to foster research groups and to create a network of them in Europe. But the last two years have been very difficult. It’s been difficult to meet. It’s not easy to generate new ideas and new activities if you cannot meet and discuss. A lot of the JPND’s activities started because we met, discussed things together, and came up with an idea.
<b>Online conferences and meetings are not the same. </b><br>Absolutely, no, no. All Europe is represented in the JPND. You can imagine that we have moments of strong friction. But being together, it was muted. It’s very difficult to do that when you’re in a Zoom meeting. We really need to go back and reconvene and start working together again.
Maggi looks back on a research career spanning decades.

<b>Looking at the next five to 10 years, what are the prospects for the development of treatments? </b><br>One of the problems is that whatever drug we devise, and we devised a few, they are given to people too late. The disorder starts 20 years before you see the symptomology. So, people have started to generate studies of healthy people, and follow them in time to identify early biomarkers. If you find the biomarker, or molecules in the blood, that reveals the first signs of the disease, you can try the drugs right away. Until we reach that point, it will be very difficult to find drugs.
<p><b>Now that you are professor emeritus, do you have any regrets?</b><br>I think I should have trusted my research more. I think that often you’re afraid of saying something that is not correct. And you do not dare to publish it. If I could go back, I would be more daring. Other than that – no.</p>
<b>Was that related to being a woman? </b><br>That is a very good question. I think that it is certainly a fact, but not a genetic thing. I think it is educational, the way we are brought up. Women are certainly more insecure, or at least women of my age. Probably it is very different now. But I think that we were not as secure as we should have been. We did not trust sufficiently in our possibilities, our power.

By Bill Hinchberger
Bill Hinchberger is a Paris-based independent journalist and a former international correspondent for The Financial Times, Business Week and other media. He has contributed to The Lancet and Science.