An aging-sensitive secreted phospholipase confers neuroprotection and cognitive resilience.

Cinzia Vicidomini, Travis D Goode, Ruilin Yu, Iyanah Mehta, Kathleen M McAvoy, Connor H Beveridge, Caitlin E Randolph, Sanjay N Iyer, Matheus B Victor, Noelle Leary, Liam Evans, Michael J Steinbaugh, Zon Weng Lai, Marina C Lyon, Manuel Rico Fernández San Silvestre, Giorgia Tosoni, Dilara Ayyildiz, Shannan Ho Sui, Kei Yamamoto, Makoto Murakami, Evgenia Salta, Li-Huei Tsai, Gaurav Chopra, Amar Sahay

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · pubmed

Paper

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.

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Research summary

The paper claims that the secreted phospholipase PLA2G2F acts as a compensatory neuroprotective signal that maintains lipid homeostasis to prevent aging-associated cognitive decline. This is relevant to longevity research because it identifies a specific molecular mechanism (lipid homeostasis via a secreted factor) that can be manipulated to bypass age-related neurodegeneration and extend cognitive healthspan, rather than merely treating downstream symptoms of Alzheimer's disease.

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