Muscle-Released Protein Offers a Promising New Path for Alzheimer’s Treatment
A new study from researchers at Florida Atlantic University and the Novo Nordisk Foundation Center for Basic Metabolic Research suggests that the key to protecting the brain from Alzheimer’s disease (AD) may not lie only in the brain itself. Instead, it may come from an unexpected place: our muscles. The research focuses on Cathepsin B (Ctsb), a muscle-released protein linked to exercise, and shows that increasing this protein specifically in muscle tissue can help preserve memory and brain function in a mouse model of Alzheimer’s.
Alzheimer’s remains one of the most devastating neurodegenerative conditions, causing progressive memory loss and cognitive decline with no curative treatment currently available. Among lifestyle factors, physical activity stands out as a strong contributor to better brain health. Because of this, scientists have spent years examining how skeletal muscle communicates with the brain. The new findings significantly push this field forward by showing how modifying a single muscle-derived protein may influence brain resilience.
The protein at the center of the study, Ctsb, has been historically known for its involvement in cancer and brain injury. More recently, it has been understood as a myokine—a molecule released by working muscles during exercise that can influence processes such as memory and neurogenesis. Earlier research has shown that exercise naturally boosts Ctsb levels, but this study specifically asked whether direct muscle-targeted expression of Ctsb could prevent cognitive decline associated with Alzheimer’s.
To answer this, researchers used a gene therapy approach. They delivered a harmless, engineered viral vector carrying the Ctsb gene directly into the muscles of mice engineered with human Alzheimer’s-related mutations. These mutations cause symptoms mimicking AD, including memory impairment and amyloid pathology. The virus introduced the Ctsb gene into muscle cells, which then began producing higher levels of the protein.
The results were striking. Mice treated with this muscle-directed Ctsb expression did not develop the usual Alzheimer’s-related memory deficits. Their learning and memory abilities remained intact compared to untreated AD-model mice. Even more impressive, the therapy preserved new neuron growth in the hippocampus—a brain region critical for forming new memories and supporting cognitive function. This preservation is especially important because adult neurogenesis is often impaired in Alzheimer’s.
On a molecular level, the treated mice showed brain, muscle, and blood protein profiles that closely resembled those of healthy mice. This suggests that increasing Ctsb in muscle has widespread beneficial effects across multiple systems. Rather than working only inside the muscle, Ctsb appears to influence the body more broadly, creating a healthier biological environment that supports memory and cognition.
Interestingly, the study found that this muscle-Ctsb treatment did not reduce hallmark Alzheimer’s features. The mice still exhibited typical AD-like inflammation and amyloid plaques, which are usually the primary targets of Alzheimer’s drugs. Yet their brain function improved despite these persistent signs of disease. This suggests that Ctsb may protect the brain through lesser-explored pathways that do not depend on reducing plaques or inflammation. The researchers note that the protein may help restore the brain’s capacity to produce essential proteins involved in adult neurogenesis, synaptic plasticity, learning, and memory.
These observations add to growing evidence that muscle and brain health are deeply interconnected. Muscles are not only mechanical tissues that help us move; they also act as endocrine organs that communicate chemical signals throughout the body. Ctsb is one such signal, and this study shows how powerful these signals can be in shaping brain resilience.
However, the effects of Ctsb were not universally positive. When healthy mice—those without Alzheimer’s mutations—were given the same muscle-targeted Ctsb treatment, the protein actually harmed their memory instead of helping it. The researchers believe this may be due to differences in how healthy muscle processes the gene therapy vector. In other words, the same intervention that helps a diseased system may disrupt a healthy one. This finding highlights the importance of precise therapeutic targeting and a deeper understanding of how Ctsb works in different physiological states.
Despite these complications, the study highlights the possibility of new treatment strategies for Alzheimer’s that focus on improving muscle health or modifying muscle-derived proteins. Potential future approaches may involve gene therapy, pharmacological agents that modulate Ctsb levels, or specialized exercise programs tailored to enhance beneficial myokines. Because exercise naturally increases Ctsb, this research also provides a biological explanation for why physically active individuals often show better cognitive aging.
While the study is limited to mice and more research is needed before translating these findings to humans, the implications are significant. It suggests that preserving brain health may begin with interventions far from the brain itself. Targeting muscle might offer a low-cost, noninvasive, and widely accessible avenue for slowing or preventing cognitive decline.
The research team included scientists from FAU’s Charles E. Schmidt College of Medicine, the Stiles-Nicholson Brain Institute, the University of Copenhagen, the University of North Carolina at Chapel Hill, and the Université Côte d’Azur in France. Their combined expertise highlights how interdisciplinary the study of muscle-brain communication has become.
To better understand the significance of this work, it’s useful to look at the broader landscape of myokines—molecules released by muscle that influence other organs. Over the past decade, researchers have identified numerous myokines involved in energy metabolism, immune regulation, and even mood. Ctsb stands out because of its strong connection to exercise-induced cognitive enhancement. When people exercise, muscle contractions stimulate the release of various proteins and peptides into circulation. Among these, Ctsb has repeatedly been linked to improved hippocampal neurogenesis and memory performance in both animals and humans.
This new study strengthens the idea that Alzheimer’s therapies may benefit from integrating system-wide biological perspectives, rather than focusing solely on the brain. It also raises important questions for future research: How exactly does muscle-derived Ctsb interact with brain cells? Does it cross the blood–brain barrier or act indirectly through other signaling pathways? How can we safely regulate Ctsb levels without causing unintended harm?
Answers to these questions will help determine whether Ctsb-based therapies become viable treatments. But for now, the findings offer an exciting and unconventional possibility—one that positions muscle health as an essential component of brain health, especially in the context of neurodegenerative diseases.
For readers interested in following the scientific details directly, the full research study is available here:
https://doi.org/10.1111/acel.70242
