Regular physical activity is known to provide many health benefits, and one of the most significant is its potential to lower the risk of developing Alzheimer's disease. A new study conducted on mice has taken a closer look at the biological processes behind this protective effect, revealing how exercise may help safeguard the brain.
Earlier research had shown that exercise raises levels of a protein called glycosylphosphatidylinositol-specific phospholipase D1, commonly known as GPLD1, in the bloodstream of mice. Scientists found that higher levels of this protein are linked to improved brain health.
GPLD1 appears to play an important role in reinforcing the blood–brain barrier, the protective layer that prevents harmful substances in the bloodstream from entering the brain. By strengthening this barrier, GPLD1 helps reduce inflammation and may slow the progression of cognitive decline.
A recent investigation led by researchers at the University of California, San Francisco uncovered a new interaction between GPLD1 and an enzyme called TNAP (tissue-nonspecific alkaline phosphatase). Normally, TNAP helps regulate the permeability of the blood–brain barrier, particularly during times of stress.
However, as organisms age, TNAP can accumulate within the cells that form the barrier. This buildup can weaken the barrier’s effectiveness and allow inflammatory substances to reach the brain. The researchers discovered that GPLD1 helps remove, or “prune,” excess TNAP from these tissues, helping maintain the barrier’s strength and protecting the brain from inflammation.
“This discovery highlights how important the rest of the body is when it comes to understanding brain aging,” explained neuroscientist Saul Villeda from UCSF.
To test the role of TNAP, the scientists genetically modified young mice so their blood–brain barrier contained unusually high levels of the enzyme. These mice developed memory and cognitive problems similar to those typically seen in older animals.
In contrast, when older mice were engineered to have lower-than-normal TNAP levels, their blood–brain barriers became less leaky, inflammation decreased, and their cognitive performance improved.
The researchers also studied mice that model Alzheimer's disease. In these animals, either increasing GPLD1 levels or lowering TNAP levels reduced the accumulation of amyloid-beta protein clumps—one of the defining features of Alzheimer’s pathology.
Inflammation and stress on neurons are widely recognized as major contributors to brain aging and diseases like Alzheimer’s. The blood–brain barrier plays a key role in preventing harmful molecules from entering the brain and triggering these processes.
This new work suggests a clear chain of events: physical exercise increases GPLD1 production, GPLD1 keeps TNAP levels under control, and this helps preserve a stronger blood–brain barrier. Together, these effects may lower the risk of cognitive decline and neurodegenerative conditions.
Understanding this mechanism could eventually lead to treatments designed to replicate the beneficial effects of exercise. According to neuroscientist Gregor Bieri of UCSF, the researchers were able to activate this protective process even late in the mice’s lives.
Although the study was conducted only in mice, scientists believe similar biological pathways may exist in humans. Future research will be needed to confirm whether the same mechanisms operate in people.
Studies like this are valuable because they not only reveal how diseases develop but also point toward possible ways to prevent or treat them.
For individuals who cannot engage in regular physical activity—particularly older adults—future therapies might one day mimic the cognitive benefits of exercise without requiring physical exertion.
While such treatments are still far away and will require extensive research and safety testing, scientists now have a better understanding of how exercise supports brain health.
“We’re uncovering biology that Alzheimer’s research has largely overlooked,” said Villeda. “It may open the door to new therapeutic strategies beyond approaches that focus solely on the brain.”
The study was published in the journal Cell.