Exercise-related muscle proteins open new avenue to treat Alzheimer’s disease

Alzheimer’s disease (AD) is a devastating cause of memory loss and cognitive decline, for which no cure exists. Among lifestyle factors, physical activity appears to be one of the strongest advocates for brain health.

There is growing evidence linking skeletal muscle function and cognitive health. Pioneering research by Florida Atlantic University and collaborators at the Novo Nordisk Foundation Center for Basic Metabolic Research takes this evidence to the next level, revealing that the key to fighting AD may not only lie in the brain, but also in our muscles.

At the center of this discovery is cathepsin B (Ctsb), a protein long studied in cancer and brain injury, but which also functions as a myokine, a molecule released by muscles during exercise, which may influence memory function.

Gene therapy in muscles shows promise

The new study, published in the journal Aging cellinvestigated whether a gene therapy approach aimed at specifically expressing Ctsb in muscle could protect brain function in an AD mouse model. In this approach, mice were given a viral vector, a harmless, modified virus containing the Ctsb gene that enters the muscle cell, where it expresses Ctsb in the tissue. These mice carry human genetic mutations that mimic key symptoms of the disease, including memory loss and amyloid pathology.

The results were striking. Mice treated with Ctsb in their muscles did not develop the typical memory deficits associated with AD. Additionally, new neuronal growth in the hippocampus, a brain region essential for learning and memory, was preserved. In fact, their brain, muscle and blood protein profiles more closely resembled those of healthy mice. This suggests that increasing Ctsb in muscle tissue could provide protection against the effects of AD.

“Our study is the first to show that specific expression of cathepsin B in muscle can prevent memory loss and maintain brain function in a mouse model of Alzheimer’s disease,” said Henriette van Praag, Ph.D., corresponding author and associate professor of biomedical sciences in the FAU Charles E. Schmidt College of Medicine and member of the FAU Stiles-Nicholson Brain Institute (SNBI).

“Our results suggest that modulating muscle Ctsb through gene therapy, and perhaps even through drugs or exercise, could slow or reverse memory decline by promoting brain cell growth, restoring protein balance, and rebalancing brain activity.”

Unexpected results and future directions

Interestingly, the treatment did not reduce the hallmark features of AD, such as inflammation or plaques, which are generally considered the main therapeutic targets. Despite these persistent signs of disease, brain function improved, indicating that Ctsb may support memory and cognition in underexplored pathways, perhaps by restoring the brain’s ability to produce proteins essential for neurogenesis, synaptic plasticity, learning, and memory in adults.

“We have long known that physical activity benefits the brain, but this study brings us closer to understanding how this happens at the molecular level,” said Atul S. Deshmukh, Ph.D., co-corresponding author and associate professor at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

“Muscle is not just a mechanical tissue, it is a powerful communicator with the brain. This opens up exciting possibilities for new treatments that harness the body’s biology to combat neurodegeneration.”

However, the effects were not the same in healthy mice. When Ctsb was administered to mice without AD, it appeared to impair their memory, potentially due to differential processing of the gene therapy vector in the muscle of healthy mice compared to that of AD mice.

Although more research is needed, particularly in humans, this study adds to a growing body of evidence that muscles and the brain are deeply connected and that improving muscle health could offer new ways to treat or even prevent neurodegenerative diseases.

“While there is still much to learn, our work reinforces a powerful idea: the path to protecting the brain may begin in the body,” van Praag said. “Targeting muscles could potentially become a new, non-invasive, low-cost therapeutic intervention for neurodegenerative diseases that would be accessible to many patients.”

Co-authors of the study include first authors Alejando Pinto, SNBI; Hazal Haytural, Ph.D., University of Copenhagen; and Cassio Morais Loss, Ph.D., SNBI. Other co-authors represent the Schmidt College of Medicine; Charles E. Schmidt College of Science, SNBI, University of Copenhagen, University of North Carolina at Chapel Hill and Institute of Molecular and Cellular Pharmacology, Université Côte d’Azur et Center National pour la Recherche Scientifique, Valbonne, France.

“These studies represent an important step in understanding the mechanisms by which exercise, and specifically muscle-derived molecules, can support brain health,” said Randy Blakely, Ph.D., executive director of SNBI, the David JS Nicholson Distinguished Professor of Neuroscience and professor of biomedical sciences at the Schmidt College of Medicine.

“By showing that signals from our muscles can profoundly influence memory and cognition, the work adds significantly to our appreciation of the complex connections between the body and the brain. The work is striking not only for its relevance to new drugs to treat Alzheimer’s disease, but also for providing a compelling example of how biological factors derived from healthy lifestyle opportunities can be identified and can support resilience to the challenges of aging.”