Published on: Feb 20, 2026
Researchers at University of California San Francisco (UCSF) have identified a biological mechanism that helps explain how exercise enhances cognitive function by reinforcing the brain’s protective blood vessel network, known as the blood–brain barrier.
As people age, the blood–brain barrier can become increasingly permeable, allowing harmful substances to enter the brain. This leakage triggers inflammation, a process strongly linked to cognitive decline and neurodegenerative diseases such as Alzheimer's disease.
Several years ago, the research team discovered that exercise prompts the liver to produce an enzyme called GPLD1, which appeared to rejuvenate the brain in mice. However, since GPLD1 cannot cross into the brain directly, scientists were initially unsure how it exerted its effects.
The new study reveals that GPLD1 acts indirectly through a protein called TNAP. With aging, TNAP accumulates in the cells that form the blood–brain barrier, contributing to its breakdown. When mice exercise, GPLD1 produced in the liver travels through the bloodstream to the brain’s surrounding vessels, where it removes excess TNAP from these cells helping restore the barrier’s integrity.
The team found that increasing TNAP levels in young mice led to cognitive decline similar to that seen in older animals. Conversely, reducing TNAP in aged mice strengthened the blood–brain barrier, lowered brain inflammation, and improved performance on memory tests even later in life.
According to senior author Saul Villeda, Ph.D., of the UCSF Bakar Aging Research Institute, the findings highlight how closely brain health is tied to processes occurring elsewhere in the body. Co-author Gregor Bieri, Ph.D., noted that targeting TNAP even in older mice successfully reversed aspects of age-related decline.
The researchers suggest that developing therapies capable of modulating proteins like TNAP could offer a new strategy for protecting or restoring the blood–brain barrier. This approach may expand Alzheimer’s research beyond traditional brain-focused treatments and open new avenues for combating age-related cognitive decline.
Source: https://www.ucsf.edu/news/2026/02/431526/scientists-find-mechanism-how-exercise-protects-brain
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