Exercise, GPLD1 and TNAP May Protect Against Alzheimer’s Disease

Exercise, GPLD1 and protection against Alzheimer’s disease

Physical activity offers numerous health benefits, including a lower risk of developing Alzheimer’s disease. New research in mice has now examined the precise mechanisms and proteins through which exercise may help safeguard the brain.

Earlier work had shown that exercise raises blood levels of a protein in mice known as glycosylphosphatidylinositol-specific phospholipase D1. This protein, more commonly called GPLD1, has been linked with healthy brain function.

GPLD1 reinforces the blood-brain barrier, the protective boundary that prevents unwanted substances in the bloodstream from reaching the brain. In doing so, it helps defend against inflammation and the cognitive decline that can follow.

A new study led by researchers at the University of California, San Francisco (UCSF) has revealed a link between GPLD1 and TNAP, or tissue-nonspecific alkaline phosphatase. Under stressful conditions, this enzyme would normally help to keep the barrier permeable.

How GPLD1 regulates TNAP in the blood-brain barrier

As time passes, however, TNAP builds up in the cells of the blood-brain barrier and disrupts how effectively they work. The researchers found that GPLD1 “prunes” TNAP from tissue, improving the brain’s defences against inflammation.

"This discovery shows just how relevant the body is for understanding how the brain declines with age," says neuroscientist Saul Villeda, from UCSF.

Young mice genetically modified to carry extra TNAP in their blood-brain barrier experienced cognitive decline resembling that seen in older mice.

Conversely, older mice genetically engineered to have lower-than-normal TNAP levels had fewer leaks in the blood-brain barrier, reduced inflammation and improved cognitive performance.

In mice modelling Alzheimer’s disease, both higher GPLD1 levels and lower TNAP levels were linked to fewer damaging clusters of amyloid beta protein, a defining feature of Alzheimer’s disease. This offered another encouraging indication.

Inflammation and stress affecting neurons are already known to play an important part in Alzheimer’s disease, brain ageing and cognitive decline. The blood-brain barrier helps block chemicals that might otherwise provoke this inflammation.

Potential treatments that mimic the benefits of exercise

The findings indicate that exercise generates GPLD1, GPLD1 controls TNAP, and this produces a more robust blood-brain barrier. In turn, that could reduce the risk of cognitive decline and conditions including Alzheimer’s disease.

Understanding this pathway could help researchers develop treatments that artificially reproduce GPLD1’s beneficial effects.

"We were able to tap into this mechanism late in life for the mice, and it still worked," says neuroscientist Gregor Bieri, from UCSF.

The fact that the research involved mice alone is a limitation. Nevertheless, comparable processes may be occurring in humans, which future studies could investigate.

Research of this kind has two benefits: it clarifies how particular health conditions begin while also providing clues about how they might be addressed.

Regular exercise is not feasible for everyone, particularly in later life. Eventually, it may be possible to create medicines that deliver exercise’s cognitive protection without requiring any physical movement.

Reaching that point will take considerable time, as much more research and safety testing are needed. Even so, the study adds to what is known about exercise’s brain-enhancing effects.

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

The research was published in Cell.