Nature Neuroscience· 2026Q1
An aging-sensitive secreted phospholipase confers neuroprotection and cognitive resilience
- 1citations
- Q1SCImago
- 2026year
Short summary
A secreted enzyme, Pla2g2f, increases in aging mouse brains and protects against cognitive decline by reducing inflammation and lipid buildup, preserving memory.
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Key points
- Pla2g2f expression increases in aging mouse brains and is associated with human cognitive resilience.
- Deleting Pla2g2f exacerbates aging-related synapse loss, neuroinflammation, and memory impairment.
- Increasing Pla2g2f in aging mice prevents these pathological changes and protects memory.
- Pla2g2f's catalytic site is essential for reducing lipid droplets, inflammation, and gliosis.
- Neuronal Pla2g2f signals to microglia to reduce lipid and cholesterol ester load.
AI-generated from the title and abstract; the full text is not read.
Abstract
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.
The authors' abstract, as published at the source. Nature Neuroscience, 2026 · DOI ↗
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Field: Physiology
PhysiologyMedicine