Exercise Boosts Brain Health by Repairing Blood-Brain Barrier, Study Finds

Researchers uncover link between physical activity and cognitive protection through liver-produced protein GPLD1.

Published on Feb. 20, 2026

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Researchers at UC San Francisco have discovered that exercise can strengthen the brain's natural defense system by repairing the blood-brain barrier. Their work suggests that the liver-produced protein GPLD1 plays a key role in this process, helping to remove a harmful protein called TNAP that contributes to barrier leakiness and inflammation as we age.

Why it matters

This breakthrough could open new avenues for Alzheimer's therapies beyond just targeting the brain, by focusing on strategies to restore blood-brain barrier function. The findings also provide a compelling reason for people to prioritize regular physical activity to support their long-term cognitive health.

The details

The blood-brain barrier naturally becomes more fragile with age, allowing damaging compounds to enter brain tissue and trigger inflammation. Scientists observed that exercise in mice led to increased levels of GPLD1, an enzyme produced in the liver. GPLD1 appears to rejuvenate the brain by targeting another protein called TNAP, which accumulates in the cells forming the blood-brain barrier and contributes to its leakiness. When mice exercise, their livers release GPLD1 into the bloodstream, which then travels to the brain's blood vessels and removes TNAP, helping to restore the barrier's integrity.

  • Several years ago, scientists observed that exercise in mice led to increased levels of GPLD1.
  • Experiments showed that genetically modifying young mice to produce excess TNAP resulted in memory and cognitive problems similar to those seen in older animals.
  • Reducing TNAP levels in older mice led to a less permeable blood-brain barrier, decreased inflammation, and improved memory performance.

The players

UC San Francisco

A public research university in San Francisco, California, known for its excellence in health sciences research.

Dr. Saul Villeda

Associate director of the UCSF Bakar Aging Research Institute and lead researcher on the study.

Gregor Bieri, PhD

A postdoctoral scholar in Dr. Villeda's lab and co-author of the study.

GPLD1

A liver-produced enzyme that appears to rejuvenate the brain by targeting the protein TNAP.

TNAP

A protein that accumulates in the cells forming the blood-brain barrier and contributes to its leakiness as we age.

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What they’re saying

“This discovery shows just how relevant the body is for understanding how the brain declines with age.”

— Dr. Saul Villeda, Associate director of the UCSF Bakar Aging Research Institute

“We were able to tap into this mechanism late in life, for the mice, and it still worked.”

— Gregor Bieri, PhD, Postdoctoral scholar in Villeda's lab

“We're uncovering biology that Alzheimer's research has largely overlooked. It may open new therapeutic possibilities beyond the traditional strategies that focus almost exclusively on the brain.”

— Dr. Saul Villeda, Associate director of the UCSF Bakar Aging Research Institute

What’s next

Developing medications that can effectively 'trim' proteins like TNAP could offer a novel approach to restoring barrier function and protecting against cognitive decline.

The takeaway

This research provides a compelling reason for people to prioritize regular physical activity as an investment in their long-term brain health, as exercise can potentially trigger the release of GPLD1 and support a stronger, more resilient blood-brain barrier.