Jay Reinstein, who suffers from Alzheimer's, prepares to receive a PET scan at MedStar Georgetown University Hospital in Washington, DC on June 20, 2023. (Photo by Michael Robinson Chávez/The Washington Post via Getty Images)
SAN FRANCISCO - Scientists at UC San Francisco have identified how exercise helps preserve brain function, discovering that a liver-produced enzyme can repair age-related leaks in the blood-brain barrier linked to cognitive decline.
The study was published in Cell on Feb. 18.
Dig deeper:
As people age, the blood-brain barrier — the system of vessels that protects the brain — can become leaky, allowing harmful substances to enter and trigger inflammation linked to memory loss and diseases such as Alzheimer’s.
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Researchers had previously discovered that exercise increases a liver-produced enzyme called GPLD1, which appears to benefit the brain in mice, but they did not know how it worked since it cannot enter the brain.
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The new study shows that GPLD1 acts indirectly by targeting a protein called TNAP. As mice age, TNAP builds up in the cells of the blood-brain barrier, making it more permeable. Exercise boosts GPLD1 levels, and the enzyme travels through the bloodstream to the vessels around the brain, where it removes excess TNAP and helps keep the barrier strong.
What they're saying:
"This discovery shows how important the body is in understanding how the brain declines with age," said Saul Villeda, associate director of the UCSF Bakar Aging Research Institute.
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The backstory:
To understand how GPLD1 works, researchers focused on its main role — cutting certain proteins from the surface of cells. They searched for tissues where these proteins might build up with age.
The blood-brain barrier stood out because its cells had several possible targets. But when scientists tested them, GPLD1 only cut one protein: TNAP.
Mice engineered to have higher levels of TNAP in the blood-brain barrier showed memory problems similar to older mice.
When researchers reduced TNAP in older mice — roughly equivalent to 70 in human years — the blood-brain barrier became less leaky, brain inflammation decreased and the mice performed better on memory tests.
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Why you should care:
The findings suggest the approach could work even later in life.
"We were able to tap into this mechanism late in life in the mice, and it still worked," said Gregor Bieri, a postdoctoral scholar in Villeda’s lab and a co-first author of the study.
Researchers say developing drugs that target proteins like TNAP could offer a new way to restore the blood-brain barrier after it has weakened with age.
"We’re uncovering biology that Alzheimer’s research has largely overlooked," Villeda said. "It may open new therapeutic possibilities beyond traditional strategies that focus almost exclusively on the brain."
The Source: The information in this story comes from a peer-reviewed study conducted by researchers at the University of California, San Francisco and published Feb. 18 in the journal Cell. This story was reported from Los Angeles.