For years, the link between physical exercise and improved cognitive function has been well-established, but the underlying biological mechanisms have remained largely elusive. Now, researchers at UC San Francisco have uncovered a key process explaining how exercise may safeguard the brain against neurodegenerative diseases like Alzheimer’s. The findings, published February 18 in the journal Cell, point to a surprising connection between the liver, the blood-brain barrier, and the brain’s ability to resist inflammation – a hallmark of Alzheimer’s disease.
The research offers a potential new avenue for therapeutic interventions, moving beyond strategies that solely focus on the brain itself. Understanding how exercise benefits brain health is increasingly critical as the global population ages and the prevalence of Alzheimer’s disease continues to rise. According to the Alzheimer’s Association, more than 6.7 million Americans are living with Alzheimer’s disease in 2024, a number projected to reach nearly 13 million by 2050. Alzheimer’s Association
The Blood-Brain Barrier and the Role of Inflammation
A central component of this newly understood process is the blood-brain barrier, a tightly packed network of blood vessels that protects the brain from harmful substances circulating in the bloodstream. As we age, this barrier naturally becomes more permeable, allowing damaging compounds to enter brain tissue and trigger inflammation. This chronic inflammation is strongly linked to cognitive decline and is frequently observed in individuals with Alzheimer’s disease.
How the Liver Steps In
Several years ago, the UCSF research team observed that exercise in mice led to increased levels of an enzyme called GPLD1 in the liver. While GPLD1 appeared to have rejuvenating effects on the brain, scientists were puzzled due to the fact that the enzyme itself cannot directly cross the blood-brain barrier. The new research clarifies this mystery, revealing that GPLD1 doesn’t need to enter the brain to exert its protective effects.
Instead, GPLD1 influences another protein known as TNAP. The study found that TNAP accumulates in the cells forming the blood-brain barrier as mice age, weakening the barrier and increasing its leakiness. 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, effectively restoring the integrity of the blood-brain barrier.
“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.
TNAP: A Key Target for Cognitive Enhancement
To pinpoint the mechanism, researchers focused on GPLD1’s known function: cutting specific proteins from cell surfaces. They identified potential GPLD1 targets in tissues that accumulate proteins with age, and cells in the blood-brain barrier stood out. Laboratory tests confirmed that TNAP was the primary protein trimmed by GPLD1.
Further experiments solidified TNAP’s role. 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 – improved blood-brain barrier function, reduced inflammation, and enhanced cognitive performance.
“We were able to tap into this mechanism late in life, for the mice, and it still worked,” said Gregor Bieri, PhD, a postdoctoral scholar in Villeda’s lab and co-first author of the study.
Implications for Future Alzheimer’s Treatments
These findings suggest that developing medications capable of reducing TNAP levels could offer a novel strategy for restoring blood-brain barrier integrity, even in individuals whose barriers have been compromised by aging. The research team believes this approach could complement existing Alzheimer’s therapies, which primarily target the brain directly.
“We’re uncovering biology that Alzheimer’s research has largely overlooked,” Villeda explained. “It may open new therapeutic possibilities beyond the traditional strategies that focus almost exclusively on the brain.”
The study was supported by grants 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.
This research provides a compelling new perspective on the interconnectedness of the body and brain, and highlights the potential of harnessing systemic factors – like those originating in the liver – to promote brain health and combat age-related cognitive decline. Further research will be crucial to translate these findings into effective therapies for Alzheimer’s disease and other neurodegenerative conditions.
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Disclaimer: This article is for informational purposes only and should not be considered medical advice. Please consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.
