New research from investigators at Florida Atlantic University (FAU) has found that a protein released by muscle during exercise can preserve memory in a mouse model of Alzheimer’s disease. The research, published in Aging Cell, details the role of Cathepsin B (Ctsb) in AD, which previously has been researched for its role in cancer, brain injury, and its associated role in cognition.
“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 senior author Henriette van Praag, PhD, associate professor of biomedical science at the Charles E. Schmidt College of Medicine, Florida Atlantic University.
Ctsb is known to act as a myokine released during physical activity. To determine whether muscle-derived Ctsb affects the cognitive decline related to AD, the FAU team sought to see if it could protect brain function in a mouse model of disease. They used a viral vector with Ctsb to allow it to enter the muscle and express it in the tissue. Four-month old mice received the viral vector after which they underwent behavior analyses.
The data from the study showed that Ctsb-treated AD mouse models showed improved motor coordination, spatial memory, and fear memory compared with untreated Alzheimer’s model mice. The researchers noted that despite the persistence of hallmark Alzheimer’s pathology, hippocampal neurogenesis was maintained in the treated mice, and proteomic profiles in the hippocampus, muscle, and plasma resembled those of wildtype mice.
These findings indicate that Ctsb may influence molecular pathways that support neurogenesis and synaptic plasticity.
“Improved memory function with Ctsb treatment in AD mice may be due in part to increased adult hippocampal neurogenesis, a highly regulatable process relevant to cognition and mood,” the researcher noted. Proteomic analyses showed increased RNA processing and cytosolic ribosomes in the hippocampus, indicating that the translational machinery needed to sustain neuronal function was restored. Additional proteins that showed increased abundance included P11, Anxa2, STAT3, and Nono, which are associated with neurogenesis and cell cycle regulation.
The research also revealed differences between Alzheimer’s and wildtype responses. Ctsb treatment impaired memory in wildtype mice, which was supported by observed proteomic changes that showed decreased mitochondrial proteins and increased coagulation processes in muscle. These effects were also observed in pathways in the hippocampus that reduce neural plasticity. This variability indicates that any potential therapeutics targeting Ctsb may only be effective in certain disease contexts.
While these are preclinical results, the research suggests potential future clinical applications. “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,” said van Praag.
Next steps in this line of research will include determining how endogenous Ctsb interacts with AAV-delivered Ctsb, as well as whether similar effects will occur in other Alzheimer’s mouse models. The investigators also hope to find our if the timing of delivering treatment affects the outcomes in the mouse models.
