Written by: Isha Verma, Ph.D.
Edited by: Jennifer Baker
Alzheimer’s disease (AD) is a neurodegenerative disease that causes the shrinkage of the brain and the death of the brain cells resulting in dementia, disorientation, mood swings, and other behavioral issues. These changes result in the loss of the person’s ability to function properly, ultimately resulting in death. About 6.5 million people in the United States age 65 and older live with AD. AD is associated with extracellular deposits of amyloid beta proteins (amyloid plaques), hyperphosphorylated Tau protein aggregates (neurofibrillary tangles), and loss of neuronal connections in the brain. Other risk factors include head injury, clinical depression, and high blood pressure.
In honor of Alzheimer’s and Brain Awareness Month (June), we talked to Dr. Henry Paulson, M.D., Ph.D., one of the leading AD researchers. Dr. Paulson is Lucile Groff Professor of Neurology at the University of Michigan and Director of Michigan Alzheimer’s Disease Center.
What is your research background? How did you enter the field of AD research?
I received my medical and doctorate degree from Yale, and during that time, I became interested in ion channels, how proteins assemble, and how they might misfold on occasion. When I went to residency in Neurology at the University of Pennsylvania, I initially thought I would be an epileptologist because I had worked on ion channels. But as soon as I started my residency, I realized I was more fascinated with neurodegenerative diseases. What grabbed me was this issue about protein misfolding and protein accumulation. In many hereditary disorders, some mutations affect how proteins adapt their shapes, and movement disorders, such as Huntington’s disease and Spinocerebellar Ataxia, seemed like a great area for this kind of work. So, I did a post-residency fellowship in movement disorders/neurogenetics. After I finished my fellowship, I joined as a faculty member at the University of Iowa, where I worked on movement disorders.
In 2007, I moved to the University of Michigan and took a broader role in neurodegenerative disease research by starting to work at the Michigan Alzheimer’s Disease Center. I realized that this work was very much up the alley of what I had already been working on, i.e., how proteins accumulate or misfold and the relationship between that misfolding and aggregation to the disease process. I began seeing patients with behavioral or cognitive issues. A little over ten years ago, I became the Director of the Alzheimer’s Disease Center, which focuses on multiple aspects of AD research.
Can you tell us a little about your lab’s research?
My lab explores why the aging brain degenerates in neurodegenerative diseases, such as AD, Frontotemporal Dementia, and polyglutamine expansion disorders, such as Huntington’s disease and Spinocerebellar Ataxia type 3 (SCA3). We are trying to understand mechanisms by which genes and proteins involved in quality control help the brain to age successfully and how when mutations occur, these quality control pathways can be disrupted to cause the problems that occur in these diseases. For example, we are interested in the fundamental role of Ubiquitin-dependent protein quality control machinery in neurons. We employ techniques ranging from cell-based assays, stem cells, organoids, engineered mouse models, and human disease tissue to address these questions.
What research projects does the Michigan Alzheimer’s Disease Center focus on?
Michigan Alzheimer’s Disease Center supports both clinical and basic research. There is a wide range of studies, from pure clinical research observational studies to clinical trials of disease-modifying medications. For example, we have studies about nonpharmacological approaches to therapy, such as brain stimulation, how people drive when they have cognitive issues, and how caregivers deal with stress. The other thing we support in the Alzheimer’s Disease Center is tons of basic research. We provide funding to young investigators, particularly those with novel ideas such as transposable elements and their role in diseases, quality control pathways in the brain, and how aberrant circuitry might alter brain function. We also have a brain bank with over 1500 brain samples available to investigators worldwide to look at the gold standard, human disease tissue. We are also looking into how the environment in which someone is born and spends their life influences the risk of developing neurodegenerative diseases. This may include exposure to pollutants, socio-economic conditions, and access to healthcare.
What is next? Where do you think the AD research field is heading?
Many proteins implicated in neurodegenerative disorders have intrinsically disordered or unfolded domains. These domains are not locked into a particular structural shape and may allow some conformational flexibility that enables these proteins to interact with many different partners. But these domains can also drive more fluid dynamic interactions of the same types of molecules, for example, phase transitions, liquid droplet formation, and biomolecular condensates. Many biological processes in the cell require these protein condensates as they serve a normal function. But disease mutations might change the dynamics of those biomolecular condensates and can elicit downstream aggregation phenomenon. So, that is an exciting area of research in AD. Another important thing is the non-amyloid contributions to brain dysfunction. We need to know more about how other factors, such as Tau, TDP-43, and alpha-synuclein contribute to AD and the role of immune and vascular factors. Michigan Alzheimer’s Disease Center has studies in all these areas.
Also, we still do not know enough about the causes of cognitive impairment and dementia in historically marginalized groups. As we develop disease-modifying therapies, the ability to tell people what their risk factors are, help them modify them, and make decisions about their lives based on risk factors is crucial. One of our areas of interest is understanding the science of how you disclose results to patients and how they then internalize and use that information in their lives.
What advice would you give to young researchers starting their careers?
I would suggest students to avoid being too cautious and go for difficult experiments. Also, you need to think about the big picture. You must care about and be interested in what you are doing. One of the exciting things about science is that you do not always know where you are going. You might have a hunch or hypothesis that you have to test and see where things go.
Isha Verma, Ph.D., is a postdoctoral research fellow at the University of Michigan Medical School. Her research is focused on understanding mechanisms of epilepsy using neural cells and brain organoids from patient-derived induced pluripotent stem cells. Dr. Verma is also an experienced science communicator and educator.
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