Exercise Boosts Brain Health by Repairing Blood-Brain Barrier, Study Finds
- Researchers have uncovered a key biological process explaining how exercise benefits brain health, potentially offering new avenues for protecting against neurodegenerative diseases like Alzheimer’s.
- As we age, the blood-brain barrier – a tightly packed network of blood vessels that shields the brain from harmful substances – naturally weakens.
- Several years ago, the research team observed that exercise in mice led to increased levels of an enzyme called GPLD1 in their livers.
Researchers have uncovered a key biological process explaining how exercise benefits brain health, potentially offering new avenues for protecting against neurodegenerative diseases like Alzheimer’s. The findings, published on , in the journal Cell, highlight a surprising connection between liver function, the blood-brain barrier, and the brain’s ability to resist inflammation.
As we age, the blood-brain barrier – a tightly packed network of blood vessels that shields the brain from harmful substances – naturally weakens. This increased permeability allows damaging compounds to enter brain tissue, triggering inflammation, a known contributor to cognitive decline and conditions like Alzheimer’s disease. The research, conducted at UC San Francisco, sheds light on a previously unknown mechanism by which exercise helps maintain the integrity of this crucial barrier.
Several years ago, the research team observed that exercise in mice led to increased levels of an enzyme called GPLD1 in their livers. While it was clear that GPLD1 had a rejuvenating effect on the brain, the mechanism remained a mystery. GPLD1 itself cannot cross the blood-brain barrier, leaving scientists puzzled as to how it exerted its protective effects.
The new study reveals that GPLD1 works by influencing another protein, TNAP. Researchers found that as mice age, TNAP accumulates in the cells that form the blood-brain barrier, contributing to its leakiness. Crucially, when mice exercised, their livers released GPLD1 into the bloodstream. This enzyme then travels to the blood vessels surrounding the brain and effectively trims TNAP from the surface of the cells, helping to restore the barrier’s protective function.
“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. “We’re uncovering biology that Alzheimer’s research has largely overlooked.”
To pinpoint TNAP’s role, the researchers investigated what GPLD1 does best: cleave specific proteins from cell surfaces. They searched for potential GPLD1 targets in various tissues and identified several proteins that accumulate with age. Cells within the blood-brain barrier stood out, carrying multiple potential targets. Laboratory testing revealed that TNAP was the only protein directly trimmed by GPLD1.
Further experiments solidified TNAP’s importance. Young mice genetically engineered to produce excess TNAP in the blood-brain barrier exhibited memory and cognitive impairments mirroring those seen in older animals. Conversely, reducing TNAP levels in older mice – equivalent to approximately 70 human years – resulted in a less permeable blood-brain barrier, decreased inflammation, and improved performance on memory tests.
“We were able to tap into this mechanism late in life, for the mice, and it still worked,” explained Gregor Bieri, PhD, a postdoctoral scholar in Villeda’s lab and co-first author of the study. This suggests a potential therapeutic window for interventions aimed at restoring blood-brain barrier function even after age-related decline has begun.
The findings suggest a novel therapeutic strategy: developing medications capable of trimming proteins like TNAP could offer a way to restore the blood-brain barrier’s integrity, even after it has been compromised by aging. This approach moves beyond traditional Alzheimer’s research, which has largely focused on interventions targeting the brain directly.
The study was supported by funding 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.