Evidence map›Paper›PMID 42881225›Full record

ArticleNature neuroscience2026

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 and 14 more

Abstract read
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In one paragraph

Article in Nature neuroscience, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

24 authors.

Cinzia VicidominiDepartment of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-4191-2850
Travis D Goode *Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-1432-8894
Ruilin Yu *Department of Chemistry, Purdue University, West Lafayette, IN, USA.ORCID http://orcid.org/0000-0002-2060-2565
Iyanah Mehta *Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0009-0002-9953-9016
Kathleen M McAvoyDepartment of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Connor H BeveridgeDepartment of Chemistry, Purdue University, West Lafayette, IN, USA.
Caitlin E RandolphDepartment of Chemistry, Purdue University, West Lafayette, IN, USA.
Sanjay N IyerDepartment of Chemistry, Purdue University, West Lafayette, IN, USA.
Matheus B VictorPicower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
Noelle LearyPicower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
Liam EvansDepartment of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Michael J SteinbaughHarvard Chan Bioinformatics Core, Harvard School of Public Health, Harvard University, Boston, MA, USA.ORCID http://orcid.org/0000-0002-2403-2221
Zon Weng LaiHarvard Chan Advanced Multi-omics Platform, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Marina C LyonDepartment of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Manuel Rico Fernández San SilvestreDepartment of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Giorgia TosoniNetherlands Institute for Neuroscience, Amsterdam, the Netherlands.ORCID http://orcid.org/0000-0003-0787-8556
Dilara AyyildizNetherlands Institute for Neuroscience, Amsterdam, the Netherlands.
Shannan Ho SuiHarvard Chan Bioinformatics Core, Harvard School of Public Health, Harvard University, Boston, MA, USA.ORCID http://orcid.org/0000-0002-6191-4709
Kei YamamotoGraduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima, Japan.
Makoto MurakamiLaboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Evgenia SaltaNetherlands Institute for Neuroscience, Amsterdam, the Netherlands.
Li-Huei TsaiBroad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-1262-0592
Gaurav ChopraDepartment of Chemistry, Purdue University, West Lafayette, IN, USA.ORCID http://orcid.org/0000-0003-0942-7898
Amar SahayDepartment of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. asahay@mgh.harvard.edu.ORCID http://orcid.org/0000-0003-0677-1693

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Identifiers

PMID42881225

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.