Muscles Send A Lifeline To The Alzheimer’s Brain

A single protein released by working muscle may help rescue memory in an Alzheimer’s ravaged brain. In a new study from Florida Atlantic University and collaborators at the University of Copenhagen, scientists used gene therapy to boost the exercise linked protein Cathepsin B (Ctsb) in skeletal muscle of Alzheimer’s disease (AD) model mice, finding that it preserved memory, supported hippocampal neurogenesis, and shifted brain wide protein networks toward a healthier state. The work, published in the journal Aging Cell, suggests that part of the path to treating Alzheimer’s may run through muscle rather than the brain alone.

Turning Muscle Into A Therapeutic Organ

Alzheimer’s is marked by progressive memory loss and cognitive decline, and available drugs offer only modest and temporary benefit. At the same time, decades of work have shown that physical activity protects brain health, with exercise improving brain volume, blood flow, and cognition. The question driving this study was simple and sharp: could a single muscle derived factor that rises with exercise be enough to shield an Alzheimer’s brain on its own?

The team focused on Cathepsin B, a lysosomal protease long associated with cancer and brain injury, but recently recognized as a myokine, a molecule released from muscle during exercise that can influence memory. Using an AAV9 viral vector, they drove expression of the mouse Ctsb gene specifically in skeletal muscle of APP/PS1 Alzheimer’s model mice starting at four months of age. These animals carry humanized mutations in amyloid precursor protein and presenilin that normally lead to plaques, gliosis, and cognitive deficits by middle age.

Six months after treatment, the mice underwent a battery of behavioral tests, including activity box, rotarod, the Morris water maze, and fear conditioning. The researchers then analyzed adult neurogenesis, plaque pathology, neuroinflammation, and proteomic profiles in hippocampus, muscle, and plasma.

“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. “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.”

Memory Protection Without Clearing Plaques

The headline result is stark. In Alzheimer’s mice, muscle targeted Ctsb treatment prevented the appearance of motor and cognitive deficits. In the Morris water maze, treated AD mice retained spatial memories that control AD mice quickly lost. In fear conditioning, their responses more closely resembled wild type controls than diseased littermates. At the cellular level, Ctsb restored the number of doublecortin positive newborn neurons in the dentate gyrus to wild type levels, indicating preserved adult hippocampal neurogenesis.

Yet the classic pathological landmarks barely budged. Amyloid plaque burden in cortex and hippocampus remained unchanged. Microglial activation, assessed by Iba1 staining, was elevated in both treated and untreated AD groups compared with controls. Astrocyte density showed no clear treatment effect. In other words, memory improved while plaques and inflammation largely stayed put.

Proteomic analyses help explain how this could be true. In the hippocampus of AD mice, Ctsb treatment boosted pathways involved in mRNA metabolism, RNA processing, and cytosolic ribosome function, hinting at a restoration of the translational machinery that neurons need to grow and adapt. The intervention also shifted the balance of glutamatergic proteins in a way that may dampen excitotoxic stress, nudging the excitatory inhibitory equilibrium toward a healthier set point in the Alzheimer’s brain.

A Double Edged Signal In Healthy Animals

The story is more complicated in wild type mice. In animals without Alzheimer’s mutations, the same muscle Ctsb treatment increased locomotor activity but harmed memory performance in the water maze and blunted fear conditioning. Muscle proteomics in these healthy mice showed reduced mitochondrial processes and increased coagulation related pathways, suggesting that in the absence of disease, chronic elevation of Ctsb may disrupt muscle and brain homeostasis instead of protecting it.

By contrast, in AD mice, Ctsb increased translation related processes in muscle and enhanced metabolic pathways in plasma. Across tissues, the proteomic profiles of treated AD mice moved closer to wild type controls, implying a partial normalization of systemic biology rather than a simple local rescue in one organ.

“These studies represent a significant step in understanding mechanisms by which exercise, and specifically muscle-derived molecules, can support brain health,” said Randy Blakely. “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.”

Rethinking Where Alzheimer’s Therapies Begin

The work does not offer an immediate therapy for people living with Alzheimer’s, and the authors are explicit about its limits. The experiments were done in one mouse model, in male animals, using a specific gene therapy timing and dose. The long term safety of increasing Ctsb, especially in healthy tissues, remains an open question. Still, the data make a clear conceptual statement: targeting muscle can reshape brain function and disease expression, even without erasing plaques or calming inflammation.

It also reframes how we think about lifestyle and biology. Exercise is not just “good for the brain” in some diffuse way; it is a trigger for molecular cascades in muscle that can, under the right conditions, send a lifeline back to vulnerable neural circuits. Ctsb emerges here as a candidate for harnessing that connection, whether through gene therapy, pharmacology, or precisely designed exercise regimens.

The study leaves you with a simple but powerful idea. Protecting the aging brain may require looking beyond the skull, into the tissues that move us through the world, and asking how their signals can be tuned to keep memory intact even as disease advances.

Journal: Aging Cell
Article: “Muscle Cathepsin B Treatment Improves Behavioral and Neurogenic Deficits in a Mouse Model of Alzheimer’s Disease”
DOI: 10.1111/acel.70242