How exercise protects the brain
Researchers have discovered a mechanism that could explain how exercise improves cognition by shoring up the brain’s protective barrier.
With age, the network of blood vessels — called the blood-brain barrier — gets leaky, letting harmful compounds enter the brain. This causes inflammation, which is associated with cognitive decline and is seen in conditions like Alzheimer’s disease.
Six years ago, the team identified a brain-rejuvenating enzyme called GPLD1 that mice produced in their livers when they exercised. But they couldn’t understand how it worked, because it cannot get into the brain.
The new study answers that question. Researchers discovered that GPLD1 was working through another protein called TNAP. As the mice age, the cells that form the blood-brain barrier accumulate TNAP, which makes it leaky. But when mice exercise, their livers produce GPLD1. It travels to the vessels that surround the brain and trims TNAP off the cells.
“This discovery shows just how relevant the body is for understanding how the brain declines with age,” said the senior author of the paper, which was published in Cell.
To begin to understand how GPLD1 works on the brain, the team considered its main job: cutting certain proteins from the surface of cells. Then, they searched for tissues that had proteins on their surface that could be cut by the enzyme. They guessed that some tissues probably accumulated more of these proteins with age.
The cells that make up the blood-brain barrier stood out. They had several GPLD1 targets dotting their surface, but when the researchers exposed of the each targets to GPLD1 in test tubes, it only cut one of them: TNAP.
Young mice engineered to have more TNAP in the blood-brain barrier lost their cognitive abilities as if they were old.
When the researchers used genetic engineering tools to reduce the amount of TNAP in 2-year-old mice — which are the equivalent of 70 human years — their blood-brain barrier became less leaky,and their brain inflammation went down. The mice also performed better on memory tests.
“We were able to tap into this mechanism late in life, for the mice, and it still worked,” said a co-first author of the study.
Finding drugs to trim proteins like TNAP could be a new way to rejuvenate the blood brain barrier,even after it’s been degraded by age.
“We’re uncovering biology that Alzheimer’s research has largely overlooked,” the senior author said. “It may open new therapeutic possibilities beyond the traditional strategies that focus almost exclusively on the brain."
