How Exercise Protects the Brain

UC San Francisco researchers have discovered a mechanism linking exercise to better brain health through a liver protein that strengthens the blood-brain barrier. With age, this barrier's network of blood vessels grows leaky, letting harmful compounds infiltrate the brain and trigger inflammation, which is associated with cognitive decline and Alzheimer's disease.

Six years back, the team identified GPLD1, a brain-rejuvenating enzyme produced by mice livers during exercise. They puzzled over its effects since GPLD1 cannot enter the brain directly. In this new study, they were able to show it operates via TNAP, a protein that accumulates on blood-brain barrier cells as mice age, causing permeability. Exercise spurs liver-made GPLD1 to reach brain-surrounding vessels and trims TNAP from those cells.

“This discovery shows just how relevant the body is for understanding how the brain declines with age,” said Saul Villeda, senior author of the study published in Cell.

To understand how GPLD1 works on the brain, the team  probed GPLD1's key task—cutting proteins from cell surfaces—and checked tissues likely to gather such proteins over time. Blood-brain barrier cells featured multiple GPLD1 targets on their surfaces. In test tubes, GPLD1 cut only TNAP.

Young mice engineered for excess TNAP in the blood-brain barrier lost cognitive skills like aged ones. Reducing TNAP in 2-year-old mice, akin to 70 human years, sealed barrier leaks, lowered brain inflammation, and sharpened memory test scores.

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

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