Scientists at the University of California, San Francisco (UCSF) have identified a molecular mechanism explaining how exercise strengthens the brain’s defenses against age-related cognitive decline, a discovery published February 18 in the journal Cell.
The research centers on the blood-brain barrier (BBB), a highly selective network of blood vessels that protects the central nervous system from harmful substances. As people age, the BBB can turn into increasingly permeable, allowing neurotoxic molecules to enter brain tissue and trigger chronic neuroinflammation – a condition strongly linked to cognitive impairment and neurodegenerative diseases like Alzheimer’s.
Several years ago, the UCSF team found that exercise increased levels of an enzyme called glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) in the livers of mice. Even as exercise-induced GPLD1 appeared to rejuvenate the brain, the mechanism remained unclear, as the enzyme itself cannot directly cross the BBB.
The new study reveals that GPLD1 indirectly fortifies the BBB by modulating tissue-nonspecific alkaline phosphatase (TNAP), a protein found on the surface of brain endothelial cells. Researchers discovered that TNAP accumulates with age, weakening the BBB and increasing its leakiness. Exercise prompts the liver to release GPLD1 into the bloodstream, where it travels to brain blood vessels and removes TNAP, restoring the barrier’s integrity.
“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 study.
To pinpoint TNAP’s role, the team found that young mice genetically engineered to produce excess TNAP in the BBB exhibited memory and cognitive deficits similar to those observed in older animals. Conversely, reducing TNAP levels in 2-year-old mice – roughly equivalent to 70 human years – improved BBB integrity, reduced 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.
The findings suggest that therapies aimed at reducing TNAP levels could offer a novel approach to restoring BBB function and mitigating age-related cognitive decline. Villeda noted that the research uncovers biological processes often overlooked in Alzheimer’s research, potentially opening new therapeutic avenues beyond those traditionally focused solely on the brain.
Other UCSF authors include Karishma Pratt, PhD; Yasuhiro Fuseya, MD, PhD; Turan Aghayev, MD; Juliana Sucharov; Alana Horowitz, PhD; Amber Philp, PhD; Karla Fonseca-Valencia; Rebecca Chu; Mason Phan; Laura Remesal, PhD; Andrew Yang, PhD; and Kaitlin Casaletto, PhD.
The study was supported by grants from the National Institutes of Health (AG081038, AG086042, AG082414, AG077770, AG067740, P30 DK063720), the Simons Foundation, the Bakar Family Foundation, the Cure Alzheimer’s Fund, the Hillblom Foundation, the Glenn Foundation, JSPS, the Japanese Biochemistry Postdoctoral Fellowship, the Multiple Sclerosis Foundation, Frontiers in Medical Research, the American Federation for Aging Research, the National Science Foundation, the Bakar Aging Research Institute, and Marc and Lynne Benioff.
