Join the Conversation with Prof. Tarja Malm

Interview

Join the Conversation with Prof. Dr. Tarja Malm

Malm Lab / Neuroinflammation Research Group, A.I. Virtanen Institute, University of Eastern Finland

Back in May 2023, we had the pleasure of having Prof. Dr. Tarja Malm present at the 3rd In-Vitro 2D & 3D Neuronal Networks Summit, the MxW Summit 2023. Dr. Tarja captivated the audience with insights into modeling brain functions with microglia-containing organoids.
Recently, we had the privilege to engage in an inspiring conversation with Dr. Tarja about her lab work and how human models and electrophysiology techniques, such as High-Density Microelectrode Arrays (HD-MEAs), are transforming Alzheimer’s disease (AD) research. This interview continues our celebration of World Alzheimer’s Day and AD advances being made by outstanding researchers, like Dr. Tarja Malm, all found in our latest MaxWell Monthly Must-Reads post.

In this conversation

The interview

Hello Dr. Tarja! Thank you for accepting our invitation for this interview. We are very excited to be speaking with you today.
To kick off our conversation, could you tell us a bit more how did your career journey led you to study neuroinflammation and AD?

I became interested in the brain during my MSc studies in Biotechnology. I have always been fascinated by how such a complex system actually works. During my internships, I explored how Tau influences neuronal functions and the impact of different Tau mutations, which led me to delve into the field of AD. For my PhD, I joined Prof. Dr. Jari Eerik Koistinaho’s group, which was investigating altered inflammatory processes in various brain diseases. My thesis focused on AD and the intriguing role of microglia – challenging yet fascinating cells to study.

Could you share more about what your lab is currently working on?
Is there anything particularly exciting you would like to highlight for us?

My lab studies microglial dysfunction in different brain diseases, with a strong focus on AD. We also explore neurodevelopment disorders like autism spectrum disorders and work on a project related to Parkinson’s disease. Understanding how human cells work has always been a key interest. When I started my own lab, I transitioned from animal modeling to induced pluripotent stem cell (iPSC) research to create models for microglia, which did not exist at the time. We established our own stem cell facility, recognizing the need to study microglia in a 3D environment, leading to the development of organoids for studying microglia-neuron interactions.

We have learned that you are now working with a human model for AD.
Could you please elaborate more on that?

In recent years, iPSC models have become crucial for studying disease mechanisms in a human context. However, these models are not ideal for AD, an age-related disease. To address this challenge, I started collaborating with Dr. Ville Leinonen at Kuopio University Hospital. He works with idiopathic normal-pressure hydrocephalus (iNPH) patients, many of whom exhibit cognitive deficits. These patients undergo brain shunt surgery to bypass cerebral spinal fluid accumulation. During surgery, a piece of brain tissue has to be removed to insert the shunt. Conveniently, the University Hospital is just next to our lab, allowing us to quickly access these biopsies. Interestingly, Dr. Ville has characterized these patient biopsies, revealing early AD-related pathology in 50% of cases, and in a span of five to ten years, a quarter of the patients develops clinical symptoms for AD. These patients provide a unique window into early AD’s brain effects before diagnosis, allowing us to study its impact on cellular functions in a living human brain.

That’s super interesting.
And how are HD-MEAs facilitating the studies with such human model for AD?

HD-MEAs have become essential to our work, due to their precision in capturing signal propagation in the human brain. Our data suggest that early AD-related changes cause a subpopulation of neurons to become hyperexcitable, leading to a subsequent loss of connectivity in the patient biopsies. As such, now we are exploring the ultrastructural level and how pathology impacts neuronal signal transmission – investigating these areas is incredibly interesting.

Yes, it definitely is!
How do you think this approach of using fresh human brain slices from biopsies will transform the science of AD?

A significant challenge in AD research is understanding brain processes, which has been limited by the availability of only end-stage postmortem tissue. Through a collaborative effort with Dr. Ville and Prof. Dr. Beth Stevens and Prof. Dr. Evan Macosko from Broad Institute – who conduct single cell sequencing studies on the same biopsies as our electrophysiological recordings –, we aim to gain an in-depth understanding of tissue ultrastructure during AD pathogenesis. I believe this knowledge will help identify therapeutic targets and address what goes wrong in the human brain, an important aspect when translating findings from animal models to human contexts.

And how do you envision the HD-MEAs supporting your research?
Meaning to find new targets or understand the functional dynamics of the brain during these early stages of AD?

As an example, in a study led by Dr. Evan Macosko, they sequenced 50 or 60 iNPH patient brains and identified specific microglia states in amyloid beta (Aβ)-positive samples. Notably, they observed a loss of neuron-derived neurotrophic factor (NDNF) neurons in layer 1, which regulate deeper layer excitatory neurons. Transcriptome data for layer 2/3 showed a hyperexcitable phenotype in the excitatory neurons at the transcriptional level. We conducted extensive sequential recordings, revealing a subpopulation of hyperexcitable neurons in layer 2/3, aligning with Dr. Macosko’s findings, and linking transcriptional and functional phenotypes for connectivity loss in the Aβ-containing biopsies.

Human excitatory cortical neurons (acute slice of brain biopsy) filled with biocytin (black) and
immunostained for Aβ plaques (green) enabling evaluation of how AD-related pathology alters neuronal morphologies.
Microscope image kindly provided by Dr. Polina Abushik, Postdoctoral researcher at Malm lab.

Super interesting that your results match with Dr. Evan’s transcriptome data.
And what do you think is the implication of such findings for the AD’s research field?

This is so far completely unknown in the field. Early AD stages exhibit hyperexcitability in brain imaging, but the underlying mechanisms remain a mystery. We are now identifying potential targets to correct the events that take place, though there is much more to uncover. We need to delve into ultrastructural changes, such as synaptic and signal transduction alterations between layer 1 and deeper layers. With HD-MEA, we aim to find these answers.

I am sure you will find them! This brings us to the end of our conversation. Thank you, Dr. Tarja, for an exciting and inspiring discussion. I think all readers like ourselves will be looking forward for more groundbreaking results and publications from the Malm’s lab.

Thank you for the opportunity. It was a pleasure.

Short Bio

Dr. Tarja Malm is a Professor in Molecular Neurobiology and the head of the Neuroinflammation research group at the A.I. Virtanen Institute, University of Eastern Finland. She is also the head of the “In vitro and ex vivo electrophysiology core facility” at the Biocenter Kuopio. Her research focuses on understanding how and why microglia become malfunctional in different neurodegenerative diseases and to elucidate the functional impact of microglia-neuron interactions. Employing interdisciplinary approaches, her group develops innovative, human based models to find therapeutic strategies to combat brain diseases.

Thank You

We would very much like to thank Dr. Tarja Malm for making time in her busy schedule for this interview. We are very appreciative of this inspiring conversation we had with her.

Discover More

If you would like to know more about Prof. Tarja’s research, please read our latest MaxWell Monthly Must-Reads featuring one of her publications in AD.
You can also learn all about MxW Summit 2023, and stay tuned for the 2024 edition!