An aging-sensitive secreted phospholipase confers neuroprotection and cognitive resilience

Key Points:

• The secreted phospholipase Pla2g2f is significantly upregulated in dentate granule cells (DGCs) following synapse loss and during aging, suggesting a role in synapse remodeling, neuron–glia communication, and lipid homeostasis in the aging brain.
• Genetic deletion of Pla2g2f in DGCs of middle-aged mice exacerbates synapse loss, increases neuroinflammation and reactive gliosis, and impairs hippocampal-dependent memory, indicating that Pla2g2f is necessary for maintaining synaptic and cognitive function during aging.
• Conversely, boosting Pla2g2f expression in DGCs in aged mice reverses synapse loss and neuroinflammation, improves dendritic spine density, enhances hippocampal-dependent memory, and modifies the trajectory of cognitive decline, supporting its neuroprotective role.
• Pla2g2f regulates lipid droplet mobilization in the dentate gyrus during aging; loss of Pla2g2f increases lipid droplet accumulation, while overexpression reduces it, with its catalytic activity required for neuron–glia signaling and lipid homeostasis.
• Human induced pluripotent stem cell-derived neuronal organoids expressing Pla2g2f modulate lipid metabolism in microglia, promoting lipid export and phospholipid remodeling, highlighting Pla2g2f's role in intercellular lipid regulation relevant to aging and neurodegeneration.