Muscle-driven gene therapy shows promise for protecting memory in Alzheimer’s

Alzheimer's disease (AD) is a devastating cause of memory loss and cognitive decline, for which no curative treatment is available. Among lifestyle factors, physical activity stands out as possibly one of the strongest defenders of brain health.

Growing evidence links skeletal muscle function to cognitive health. Pioneering research from Florida Atlantic University and its 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 lie not just 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 that also functions as a myokine – a molecule released by muscles during exercise, which can influence memory function. The new study, published in the journal Aging Cell, investigated whether a gene therapy approach to specifically express Ctsb in muscle could protect brain function in an AD mouse model. In this approach, the mice were given a viral vector – a harmless, engineered 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 the key symptoms of the condition, including memory loss and amyloid pathology.

The findings were striking. Mice treated with Ctsb in their muscles did not develop the typical memory deficits associated with AD. Moreover, the new neuron 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 may offer protection against the effects of AD.

"Our study is the first to show that expressing Cathepsin B specifically 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 an associate professor of biomedical science in the FAU Charles E. Schmidt College of Medicine and a member of the FAU Stiles-Nicholson Brain Institute (SNBI). "Our findings suggest that modulating muscle Ctsb through gene therapy, and perhaps even drugs or exercise – could slow down or reverse memory decline by promoting brain cell growth, restoring protein balance and rebalancing brain activity."

Interestingly, the treatment did not reduce the hallmark AD features, 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 through as of yet sparsely explored pathways – possibly by restoring the brain's ability to produce proteins essential for adult neurogenesis, synaptic plasticity and learning and memory.

"We've long known that physical activity benefits the brain, but this study brings us closer to understanding how that happens at a molecular level," said Atul S. Deshmukh, Ph.D., co-corresponding author and an associate professor at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen. "Muscle isn't just a mechanical tissue – it's a powerful communicator with the brain. This opens exciting possibilities for new treatments that harness the body's own biology to fight neurodegeneration."

The effects, however, were not the same in healthy mice. When Ctsb was given to mice without AD it appeared to harm their memory, potentially due to differential processing of the gene therapy vector in healthy versus AD mouse muscle.

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

"While there's still much to learn, our work reinforces a powerful idea: the path to protecting the brain may start in the body," said van Praag. "Targeting muscle may have the potential to become a novel, low cost, non-invasive therapeutic intervention for neurodegenerative disease that would be accessible to many patients."

Study co-authors 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 Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur & Centre National pour la Recherche Scientifique, Valbonne, France.

"These studies represent a significant step in understanding mechanisms by which exercise, and specifically muscle-derived molecules, can support brain health," said Randy Blakely, Ph.D., executive director of the SNBI, the David J.S. Nicholson Distinguished Professor in Neuroscience, and a professor of biomedical science in 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 links between body and brain. The work is striking not only in its relevance for new medications to treat Alzheimer's disease, but also as a cogent example of how biological factors derived from healthy lifestyle opportunities can be identified and may support resilience to the challenges of aging."

The work was supported by grants from the Novo Nordisk Foundation to Deshmukh, the National Institutes of Health awarded to co-author Tal Kafri, M.D., Ph.D., University of North Carolina School of Medicine; and by the Ed and Ethel Moore Alzheimer's Disease Research Program of the Florida Department of Health awarded to van Praag.