Tell us about your research!
“In Alzheimer’s disease, there is a progressive accumulation of aggregated proteins, such as amyloid-β, which is known to form plaques, but this process starts long before symptoms arise. By the time patients have cognitive symptoms, many changes have already occurred in neurons and synapses. Despite the fact that the disease was discovered more than a century ago, there still remains a lot unknown, but it’s also interesting how many of the observations made back then, such as neuritic plaques by Oskar Fischer, are still relevant today.
In my thesis work, we try to understand what happens early in the disease. Experimental Alzheimer’s disease research is often centered on amyloid-β plaques outside neurons and what’s occurring around them. However, research from our groups show that amyloid-β forms aggregates inside the neurons before plaques are formed. This can lead to synaptic problems, and neuroinflammatory alterations can also be detected around the same time.
My thesis expands on this work by considering the interplay of neurons and microglia, the brain’s major immune cell, in the context of Alzheimer’s pathology. For instance, I investigate microglia-neuron interactions and how this is affected by amyloid-β aggregates inside the neurons. The role of neuroinflammation in this context is largely unknown but has been gaining interest in the field."
What did you discover?
“My thesis work indicates that environmental triggers can modulate the intracellular accumulation of amyloid-β. One concrete example is stress. We used maternal separation in mice to model early life stress. In this protocol, pups are separated from their mother for three hours a day during their first two weeks of life. When the pups were a bit older, we could see that this experience increased the amyloid-β levels in the brain tissue and inside the neurons. Early-life stress also affected the microglial cells and levels of inflammatory markers in brain regions relevant for memory. Moreover, synaptic proteins – necessary for signaling between neurons – were decreased. Interestingly, the cellular and molecular effects of early-life stress differed between males and females. Males seemed more prone to having an altered inflammatory response whereas females had more effects on amyloid-β processing.”
Many Alzheimer’s disease researchers focus solely on brain regions like the hippocampus. But your favorite area to investigate seems to be the mammillary bodies. What amazes you about this particular region?
“I wouldn’t say my favorite, but it is an interesting area because of how understudied the region is even though it’s involved in memory. This area caught my attention in the beginning of my PhD studies when I was figuring out my project. I noticed some amyloid-β aggregates there when I was doing tests with some sections from a previous lab member and considered that the signal may not necessarily be an artifact. When scanning through the literature and comparing with brain atlases, I realized that the signal was real and there were hints that it even occurred in patients with Alzheimer’s disease, which further triggered my curiosity.
The mammillary bodies are small protrusions at the bottom of the brain. They are considered a part of the limbic system, specifically the Papez circuit, and are part of the hypothalamus. As part of this circuit, the mammillary bodies play a particular role in spatial memory with connections to other regions important to memory: the hippocampus and anterior thalamus. Thus, we hypothesized that the amyloid-β in the mammillary bodies comes from the long projection neurons that terminate in this region.
Relative to other brain regions, the major connections to and from the mammillary bodies are fairly simple. They have relatively few straightforward connections, and this makes it easier to study but also to manipulate. All in all, I have spent a large part of my Ph.D. looking into the mammillary bodies and what it could reveal about the development of axonal amyloid-β aggregates in the disease. There, I found that the axonal amyloid-β likely originates from the subiculum and that both microglial and astrocytic processes interact with this early aggregated amyloid-β."
Why is your project important?
“For Alzheimer’s disease, the more that we understand about the earliest stages, the better chances that we will have to develop more effective therapeutics that can ultimately prevent the disease from progressing to the stage when neurons are already lost and patients are already suffering from symptoms – that point of no return.”
Can you tell us more about the cover of your thesis?
“It’s a reference to an old video game called Space Invaders but here microglia are the aliens and the neuron is the ship that the player controls. There are also other nods to the game that have been adapted for the analogy that I’m trying to tell here: where there would be hearts to denotes the number of lives the player has left, I put a brain, and there are candles where the score would be as a nod how increasing age increases the risk for Alzheimer’s. I dive more into the analogy in the introduction of my thesis."
What has been the most challenging during your Ph.D.?
“Getting myself to do things on time and at a consistent pace. Working from home helped me a lot in the beginning when I needed to write. I do always manage to get things done, but with the way I am, getting it done often means an intense sprint at the end, which I do not recommend.”
And the most rewarding?
“Being a shared PhD in two of MultiPark’s research groups has been extremely rewarding. Unlike other PhD students, I also have the task of bringing the two groups closer together and promoting collaboration between people, which gives an additional sense of fulfillment. Now, we have yearly team-buildings and regular research interactions together, and I love seeing the two groups interacting with each other and their connection strengthen.”
Do you think being in two groups is a winning concept for Ph.D. students?
“Definitely! Certainly, all Ph.D. students have co-supervisors, but too many PhD students who I know do not have regular interactions with their co-supervisors. The intention of the doctoral system here – requiring co-supervisors – is good but sometimes does not benefit the student beyond the paperwork needed to start a PhD. To have access to two equally active supervisors is an invaluable resource. The two supervisors complement each other, both in knowledge and scheduling. All groups and leaders have their strengths and weaknesses, and by having two that can also collaborate, there is a broader perspective to be gained.”
What are you most proud of?
“Being able to build up to the knowledge that I have now so that I can help others with their experiments. In my project, I have done a lot of immunolabeling, confocal microscopy and 3D visualization with the software IMARIS, so I can confidently help others with these things who are just starting or don’t use these methods so often.”
What advice do you want to give to new Ph.D. students?
“Start writing early and do not wait to fill in your portfolio nor write your thesis. Do this regularly, for example, once a month.”
What happens after your defense?
“In the future, I hope to stay in the environment as a resource to help others with their research. I already do this regularly, especially with the few techniques that I have specialized in, and I enjoy using my knowledge to help others. Still, I’m open to any suggestions or ideas of what kind of position or path that I could take based on this interview, I would love to hear them!”
