SUMMARY Cognitive reserve theory posits a role for compensatory mechanisms in the aging brain in moderating cognitive decline and risk for Alzheimer’s Disease (AD). However, the identities of such mechanisms have remained elusive. A screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors identified a secreted phospholipase , Pla2g2f , whose expression increases in DGCs during aging. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation and hippocampal-dependent memory loss. Conversely, boosting Pla2g2f in DGCs during aging is sufficient to preserve synapses, reduce inflammatory microglia and reactive gliosis, prevent hippocampal-dependent memory impairment and modify trajectory of cognitive decline. Ex vivo, neuronal-PLA2G2F mediates intercellular signaling to decrease lipid droplet burden in microglia. Boosting Pla2g2f expression in DGCs of an aging-sensitive AD model reduces amyloid load and improves memory. Our findings implicate PLA2G2F as a compensatory neuroprotective factor that counteracts aging-associated cognitive decline. Highlights Pla2g2f expression is increased in DGCs following synapse loss and during aging Pla2g2f levels determine aging-associated pathophysiology and cognitive resilience PLA2G2F maintains lipid homeostasis Boosting Pla2g2f expression improves memory in an aging-sensitive AD mouse model

An aging-sensitive compensatory secretory phospholipase that confers neuroprotection and cognitive resilience