Researchers at the University of California, San Francisco, have discovered a mechanism by which exercise helps protect the brain from age-related damage associated with Alzheimer's disease. Physical activity prompts the liver to release an enzyme that repairs the blood-brain barrier, reducing inflammation and improving memory in older mice. The findings, published in the journal Cell, highlight a body-to-brain pathway that could lead to new therapies.
As people age, the blood-brain barrier, a network of blood vessels that protects the brain from harmful substances, often becomes leaky. This allows damaging compounds to enter brain tissue, causing inflammation linked to cognitive decline and conditions like Alzheimer's disease.
A team led by Saul Villeda, PhD, associate director of the UCSF Bakar Aging Research Institute, investigated this process. Several years ago, they found that exercising mice produced higher levels of an enzyme called GPLD1 in their livers. Although GPLD1 cannot cross into the brain, the researchers recently uncovered its role: it targets a protein known as TNAP, which accumulates in blood-brain barrier cells with age, weakening the barrier.
When mice exercise, GPLD1 enters the bloodstream and removes TNAP from the surface of these cells, restoring the barrier's integrity and reducing inflammation. Experiments showed that young mice genetically modified to overproduce TNAP exhibited memory and cognitive issues similar to those in older animals.
In older mice, equivalent to about 70 human years, lowering TNAP levels made the barrier less permeable, decreased inflammation, and enhanced performance on memory tests. "We were able to tap into this mechanism late in life, for the mice, and it still worked," said Gregor Bieri, PhD, a postdoctoral scholar in Villeda's lab and co-first author of the study.
"This discovery shows just how relevant the body is for understanding how the brain declines with age," Villeda noted. The research suggests that drugs mimicking GPLD1's action on proteins like TNAP could help restore the blood-brain barrier in aging humans. "We're uncovering biology that Alzheimer's research has largely overlooked," Villeda added, pointing to potential therapies beyond brain-focused approaches.
The study was published on February 18 in Cell.
