Exercise and Brain Health: How a Liver Protein Protects Against Cognitive Decline

Researchers at UC San Francisco have uncovered a key mechanism explaining how exercise benefits brain health, revealing a surprising link between physical activity, the liver, and the brain’s protective barrier. The findings suggest that exercise fortifies the brain’s defenses against age-related damage, potentially offering new therapeutic avenues for conditions like Alzheimer’s disease.

The Blood-Brain Barrier and Cognitive Decline

As we age, the blood-brain barrier – a tightly packed network of blood vessels that shields the brain from harmful substances – can become increasingly fragile and “leaky.” This leakiness allows damaging compounds to enter brain tissue, triggering inflammation, a known contributor to cognitive decline and conditions like Alzheimer’s disease.

The Role of GPLD1: A Brain-Rejuvenating Enzyme

Several years ago, the research team identified an enzyme called GPLD1, produced in the liver during exercise, that appeared to rejuvenate the brain in mice. However, the mechanism behind this benefit remained a mystery, as GPLD1 itself cannot directly enter the brain. Previous research indicated that levels of this protein in the blood correlated with improved cognitive function in aged mice and were likewise elevated in regularly exercising elderly humans.

How GPLD1 Works: Targeting TNAP

The new research, published in Cell on February 18, reveals that GPLD1 exerts its protective effects by influencing another protein called TNAP. As mice age, TNAP accumulates in the cells forming the blood-brain barrier, weakening it and increasing permeability. When mice exercise, their livers release GPLD1 into the bloodstream. This enzyme then travels to the blood vessels surrounding the brain and removes TNAP from the surface of those cells, helping to restore the barrier’s integrity. This process effectively strengthens the blood-brain barrier, improving memory and slowing age-related decline.

Implications for Alzheimer’s and Brain Aging

“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. The findings suggest that developing medications capable of trimming proteins like TNAP could offer a new strategy to restore the blood-brain barrier, even after it has been weakened by aging.

“We’re uncovering biology that Alzheimer’s research has largely overlooked,” Villeda added. “It may open new therapeutic possibilities beyond the traditional strategies that focus almost exclusively on the brain.”

Further Research and Findings

Researchers found that young mice genetically modified to produce excess TNAP in the blood-brain barrier exhibited memory and cognitive problems similar to those seen in older animals. Conversely, reducing TNAP levels in older mice (equivalent to 70 human years) improved blood-brain barrier function, decreased inflammation, and enhanced memory performance. These results demonstrate the potential for late-life intervention to restore cognitive function.

The study was supported by grants from the National Institutes of Health, the Simons Foundation, the Bakar Family Foundation, Cure Alzheimer’s Fund, and others.