As people age, this barrier becomes leaky, allowing harmful compounds to enter the brain. This triggers inflammation, which is linked to cognitive decline and conditions such as Alzheimer’s disease.

Six years ago, the UCSF team identified a brain-rejuvenating enzyme called GPLD1, produced in the liver of mice during exercise. However, its exact mechanism remained unclear, as the enzyme cannot cross into the brain directly.

The new research reveals that GPLD1 exerts its effects through another protein called TNAP. In aging mice, cells forming the blood-brain barrier accumulate TNAP, causing leakiness. Exercise prompts the liver to produce GPLD1, which travels to the vessels surrounding the brain and removes TNAP from the cells.

“This discovery shows just how relevant the body is for understanding how the brain declines with age,” said Saul Villeda, PhD, associate director of the UCSF Bakar Aging Research Institute and senior author of the paper, published in Cell on February 18.

To understand how GPLD1 impacts the brain, the team examined its main function: cutting certain proteins from the surface of cells. They looked for tissues where these proteins accumulate with age and found that the cells of the blood-brain barrier were rich in GPLD1 targets. Testing each target in vitro revealed that GPLD1 specifically cleaves TNAP.

Young mice genetically engineered to overexpress TNAP in their blood-brain barrier displayed cognitive deficits similar to aged mice. Conversely, when researchers reduced TNAP levels in two-year-old mice (roughly 70 human years), their blood-brain barrier became less leaky, brain inflammation decreased, and memory performance improved.

“We were able to tap into this mechanism late in life for the mice, and it still worked,” said Gregor Bieri, PhD, postdoctoral scholar and co-first author of the study.

The findings suggest that developing drugs to selectively trim proteins like TNAP could rejuvenate the blood-brain barrier, even after age-related degradation.

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