PLA2G2F is Protective of Memory Function in the Aging Brain
Researchers here identify the gene PLA2G2F as a regulator of compensatory responses to some of the damage and dysfunction of aging. The researchers were primarily investigating a population of neurons found in the hippocampus, involved in memory function, but find that the gene is relevant in supporting cells of the brain also, such as microglia. Expression of PLA2G2F increases with age, and artificially increasing expression over natural levels produces greater protection. PLA2G2F appears to be involved in maintenance of normal lipid metabolism. Evidence suggests that dysfunctions in lipid metabolism occur in the aging brain, and cause harm via provoking greater inflammatory behavior in a number of supporting cell populations.
Cognitive reserve theory posits that compensatory mechanisms during aging stave off cognitive decline and lower risk for Alzheimer's disease. Here, in a screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors in mice, we identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging and is associated with cognitive resilience in humans. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes, including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation, lipid droplet accumulation, and hippocampal-dependent memory loss.
Conversely, boosting Pla2g2f in DGCs during aging is sufficient to prevent these pathophysiological alterations in hippocampal-cortical circuits, protect memory, and prophylactically modify trajectory of cognitive decline. Mutagenesis of the catalytic site of PLA2G2F prevented lipid droplet mobilization and reduction of reactive gliosis and inflammatory microglia. Neuronal PLA2G2F mediates intercellular signaling to decrease lipid droplet and cholesterol ester load in human induced pluripotent stem cell-derived microglia. Our findings implicate PLA2G2F as a compensatory neuroprotective broadcast signal that maintains lipid homeostasis to counteract aging-associated cognitive decline.