Mueller Leads Step Toward Stopping Alzheimer's Early in Its Tracks

A Northern Michigan University alumna conducted research that may help scientists achieve an elusive goal in medicine: stopping Alzheimer's disease before it irreversibly damages the brain. Rebecca (Dangremond) Mueller helped to develop an innovative laboratory model that could enable researchers to observe some of the earliest cellular changes linked to Alzheimer's. Those changes, which occur long before widespread brain cell death, are increasingly viewed as the most promising targets for future treatments. Her story is one of several innovaton-related features in the summer issue of Northern Magazine.

Mueller was the lead author on the resulting research paper, which was published in the journal Scientific Reports. The study focused on how a tau protein behaves inside brain cells, and how its malfunction may trigger the initial stages of the disease.

"With Alzheimer's, tau clumps together and folds into abnormal shapes," explained Mueller, who earned two NMU degrees: a bachelor's in 2013 and a master's in 2016. "The pattern of accumulation and where it spreads in the brain correlate to cell dysfunction and degeneration. While we know that pathological tau is a problem, the gap lies in the mechanisms behind it. How is this abnormal tau causing problems at the cellular level?"

Alzheimer's is a progressive neurodegenerative disorder and the most common form of dementia. It impacts memory, thinking and behavior. According to the Alzheimer's Association, an estimated 7.4 million Americans age 65 and older are living with the disease this year. Of those, 74% are age 75 or older.

Mueller completed the research as part of her doctoral program at Michigan State University. She and her mentor, Professor Nicholas Kanaan, planned the experiment and Mueller executed it with collaboration from Assistant Professor Benjamin Combs. The practical implications of her work are significant. Replicating very early dysfunction in a controlled laboratory setting gives scientists the opportunity to test potential therapies aimed at stopping the disease before neurons begin to die.

"We extracted abnormal forms of tau from the brains of humans with Alzheimer's and applied those to mouse neurons in a dish," she said. "This is important because it made the mouse cells accumulate the bad forms of tau, and that allowed us to study what things happen when the bad tau is present."

Mueller's team discovered two key findings. One relates to the synapses, which are the sites of communication between neurons. The cells showed early synapse loss and abnormal signaling patterns, meaning the cells weren't communicating with each other correctly. These are two of the earliest changes in the progression of Alzheimer's.

To assess synaptic function, or cell signaling, Mueller employed a high-density microelectrode array, a specialized recording device that measures cellular and network activity. She developed an inventive protocol that adapted the technology specifically for her lab's purpose, enabling the team to detect subtle changes in how brain cells communicate.

The second key finding of her research was that the cells developed swellings containing abnormal tau along the axon, the long structures that act like highways for transporting materials back and forth from the cell body to the synapse.

"These swellings suggest breakdowns in that transport system," Mueller said. "We developed an innovative model to study the early mechanisms of how tau causes toxicity in cells as a step toward potentially stopping problems before the cells die. Once neurons are gone, it's too late, so it would be amazing to target these earlier changes. From a therapeutic development standpoint, our model could be useful for testing inhibitors that could be applied to cells to prevent the tau from clumping. The system also allows scientists to add other stressors, such as forced aging of the cells or additional Alzheimer's proteins, to better understand how the disease progresses."

Mueller's effort to clarify mechanisms related to Alzheimer's could translate to other neurodegenerative conditions. At Northern, she researched the role of axon transport problems in ALS, also known as Lou Gehrig's disease, in Professor Erich Ottem's lab.

"He was a supportive and invested mentor who saw potential in me before I did and often pushed me out of my comfort zone. He wrote strong letters for my PhD program applications. He and John Rebers also wrote strong letters of support for the highly competitive NIH Ruth L. Kirschstein National Research Service Award that helped fund the research project at MSU. Erich continues to support me now. He invited me to give a talk at NMU in February, and he even officiated my wedding!

"When I picture the halls of the Biology Department, I see open doors. I always felt comfortable poking my head in to ask a question or just to talk. Everyone was very supportive. The smaller size meant more opportunities. I taught labs for five semesters and gained critical expertise on a number of microscopes that I was able to carry into my PhD research. I liked that my master's degree allowed me to gain expertise in several areas of biology while working on neuroscience research. I believe my broader background helped me. Overall, the extensive hands-on research experience, close-knit academic community and my mentor Erich prepared me well for the next step."

Mueller got offers for all seven PhD programs she interviewed for, and settled on Professor Kanaan's lab at MSU. She said he was studying axon transport in the context of Alzheimer's, so her related Northern project related to ALS folded nicely into that. Mueller completed her doctorate in 2024.

Now living in Grand Rapids, she is taking a break from full-time research until her 5-year-old son enrolls in kindergarten. She plans to return to science, ideally in microscopy, the technical field of using microscopes to view samples and objects otherwise not visible to the naked eye.

"A lot of times your data is generated by taking pictures of cells. The higher the quality of imaging you obtain through the microscope, the better your data is going to be. I think it's a really critical step in the research process, and I like the idea of people helping people achieve better visualization to make their science stronger. My long-term goal is to help support a wide range of scientific projects, potentially by running a microscopy core facility that assists multiple research groups."

Mueller's coauthored Scientific Reports publication can be viewed here.

This story was written by Kristi Evans, NMU News Director. Read other features in Northern Magazine's summer "Journeys to Innovation" issue here.