Higher Purity of Phosphatidylserine Improves Human Cortical Neuron Function by Modulating SIRT1-PGC-1α Pathways

While phosphatidylserine (PS) is recognized for its neuroprotective properties, the effects of PS purity on human cortical neurons remains unexplored. This study investigates three different PS purities (15 µM of 50%, 70%, and 80%) on neuronal health using human embryonic stem cell-derived cortical neurons. Our findings reveal that higher PS purity enhances the expression of key regulatory proteins SIRT1 and PGC-1α, known for their roles in neuroprotection and mitochondrial function. Specifically, 80% purity PS significantly increases SIRT1 and PGC-1α levels, suggesting that PS purity strengthens neuroprotective pathways and improves mitochondrial quality control. Through SIRT1 knockdown experiments, we demonstrate that PS-induced upregulation of PGC-1α is SIRT1-dependent, highlighting a SIRT1-PGC-1α regulatory axis that enhances mitochondrial health. In an amyloid-beta (Aβ42)-induced Alzheimer’s disease (AD) model, PS treatment, particularly at 70% and 80% purity, reduced cytotoxicity and countered the Aβ42-induced downregulation of SIRT1 and PGC-1α, indicating PS’s role in preserving neuronal viability and combating AD-like pathology. Further analyses showed that PS purity modulates mitochondrial fission and fusion gene expression, which are often dysregulated in neurodegenerative diseases, thereby restoring mitochondrial integrity and reducing oxidative stress. These results emphasize the importance of PS purity in human cortical neuron models and suggest that PS, as a nutritional supplement or a potential treatment for early Alzheimer’s patients, could be applied effectively in neurodegeneration strategies, targeting mitochondrial dysfunction.