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Exerkine GPLD1 bridges liver and brain
Abel Plaza-Florido1, Pedro Carrera-Bastos2, Alejandro Lucia3
1Research Center for Exercise Medicine and Sleep/Pediatric Exercise and Genomics Research Center, Department of Pediatrics, School of Medicine, University of California, Irvine, Irvine, CA, USA.
Cell Metabolism
|May 6, 2026
Summary
Exercise boosts a liver enzyme (GPLD1) that improves brain health by enhancing cognition and reducing Alzheimer's pathology. This discovery highlights the liver-brain connection in exercise-induced neuroprotection.
Area of Science:
- Neuroscience
- Metabolic research
- Gerontology
Background:
- Exercise is known to benefit brain health.
- The specific molecular mechanisms linking exercise to neuroprotection are not fully understood.
- The role of the liver in mediating exercise's effects on the brain requires further investigation.
Purpose of the Study:
- To investigate the role of hepatic glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) in mediating exercise-induced neuroprotection.
- To elucidate the enzymatic pathway connecting liver function to brain health.
- To explore the potential of targeting this pathway for cognitive enhancement and Alzheimer's disease prevention.
Main Methods:
- Measurement of hepatic GPLD1 levels following exercise interventions.
- Analysis of GPLD1's enzymatic activity on tissue-nonspecific alkaline phosphatase (TNAP).
- Assessment of cognitive function and Alzheimer's-related pathology in relevant models.
Main Results:
- Exercise was found to significantly elevate hepatic GPLD1 levels.
- GPLD1 was shown to cleave endothelial TNAP, suggesting a direct molecular interaction.
- This enzymatic activity correlated with rejuvenated cerebrovascular signaling, enhanced cognition in aging, and reduced Alzheimer's pathology.
Conclusions:
- A novel liver-to-brain enzymatic axis involving GPLD1 and TNAP mediates exercise-induced neuroprotection.
- Hepatokines like GPLD1 are potent regulators of brain resilience.
- Systemic metabolism plays a critical role in maintaining brain health and preventing age-related cognitive decline.
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