An aging-sensitive secreted phospholipase confers neuroprotection and cognitive resilience
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.
Authors
- Amar Sahay (ORCID: https://orcid.org/0000-0003-0677-1693)
- Travis D. Goode (ORCID: https://orcid.org/0000-0003-1432-8894)
- Zon Weng Lai (ORCID: https://orcid.org/0000-0003-0402-5662)
- Connor H. Beveridge
- Sanjay Iyer
- Li‐Huei Tsai (ORCID: https://orcid.org/0000-0003-1262-0592)
- Dilara Ayyildiz (ORCID: https://orcid.org/0000-0002-8627-4648)
- R. Yu (ORCID: https://orcid.org/0000-0002-2060-2565)
- Michael J. Steinbaugh (ORCID: https://orcid.org/0000-0002-2403-2221)
- Matheus B. Victor (ORCID: https://orcid.org/0000-0003-4364-4028)
- Gaurav Chopra (ORCID: https://orcid.org/0000-0003-0942-7898)
- Giorgia Tosoni (ORCID: https://orcid.org/0000-0003-0787-8556)
- Cinzia Vicidomini (ORCID: https://orcid.org/0000-0003-4191-2850)
- Noelle Leary
- I. K. Mehta (ORCID: https://orcid.org/0009-0002-9953-9016)
- Kathleen M. McAvoy
- Caitlin E. Randolph (ORCID: https://orcid.org/0009-0002-5010-2075)
- Marina C. Lyon
- Shannan J. Ho Sui (ORCID: https://orcid.org/0000-0002-6191-4709)
- Liam Evans
- Evgenia Salta
- Kei Yamamoto
- Manuel Rico Fernández San Silvestre
- Makoto Murakami
Institutions
- Broad Institute (US)
- Netherlands Institute for Neuroscience (NL)
- Harvard University (US)
- Purdue University West Lafayette (US)
- Massachusetts General Hospital (US)
- Harvard Stem Cell Institute (US)
- Purdue University Institute for Cancer Research
- Massachusetts Institute of Technology (US)
- The University of Tokyo (JP)
- Tokushima University (JP)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2026-10-15
- DOI
- https://doi.org/10.1038/s41593-026-02465-z
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00