Mass General Brigham Ventures LLC
10/15/2026 | Press release | Distributed by Public on 10/15/2026 03:38
Research Spotlight: A brain-protective molecule may help preserve memory during aging
Research Spotlight: A brain-protective molecule may help preserve memory during aging
Published October 15, 2026
Cinzia Vicidomini, PhD, and Amar Sahay, PhD, of the Mass General Brigham Department of Psychiatry, the Harvard Stem Cell Institute and the Broad Institute of Harvard and MIT, are the lead and senior authors of a paper published in Nature Neuroscience, "An aging-sensitive secreted phospholipase confers neuroprotection and cognitive resilience. Open external link in a new window "
Q: What challenges or unmet needs make this study important?
As humans age, both protective and harmful biological processes shape brain health. When the balance shifts in favor of harmful processes, age-related changes in the brain can accelerate, including synapse loss, disruptions in lipid metabolism and chronic inflammation.
One contributor to neuroinflammation appears to be the buildup of lipid droplets inside microglia, the brain's immune cells. As lipid droplets accumulate, microglia become less effective at clearing waste, maintaining synapses and supporting neurons.
These harmful changes can speed up cognitive decline and increase a person's risk of conditions like mild cognitive impairment and Alzheimer's disease. That's why it's so important for scientists to study the biological mechanisms that may help offset them. In this paper, we sought to identify the protective factors that contribute to cognitive resilience during aging.
Q: What methods or approach did you use?
Scientists have long recognized that synapse loss in the hippocampus, a brain region critical for memory, is a defining feature of age-related cognitive decline. To better understand this process, we designed a study to identify genes that are activated in response to synapse loss in the hippocampus of mice.
Q: What did you find?
We discovered a gene called Pla2g2f, which produces a secreted enzyme known as a phospholipase. Before this study, its role in the brain was not known.
We found that Pla2g2f levels increase in the hippocampus during aging and under conditions of brain inflammation. This included older adults who showed signs of Alzheimer's disease pathology in their brains but remained cognitively resilient.
To understand the gene's function, we used genetic and viral tools to either decrease or increase Pla2g2f levels in the brains of aging mice. When Pla2g2f was reduced, multiple features of brain aging became worse, including synapse loss, inflammation, impaired maturation of new brain cells, disruptions in lipid metabolism, accumulation of lipid droplets in neurons and microglia and memory impairment.
In contrast, increasing Pla2g2f levels protected against many of these changes and helped preserve memory. Remarkably, boosting Pla2g2f in middle-aged mice before they developed substantial cognitive decline altered the trajectory of age-related memory loss.
We also found that Pla2g2f influenced biological processes beyond synapse maintenance. In human microglia, increasing Pla2g2f activity reduced the accumulation of lipid droplets and cholesterol esters, two features commonly observed in microglia in Alzheimer's disease.
Q: What are the real-world implications, particularly for patients?
Aging is the greatest risk factor for Alzheimer's disease.
Our findings suggest that increasing Pla2g2f activity during aging could potentially help maintain cognitive resilience and delay or prevent the onset of mild cognitive impairment and Alzheimer's disease. Additional studies will be needed to determine whether this approach can be safely translated into therapies for patients. We are actively exploring potential ways to safely increase Pla2g2f levels in the aging brain and in Alzheimer's disease as a possible therapeutic strategy.
Authorship: In addition to Vicidomini and Sahay, Mass General Brigham authors include Travis Goode, Iyanah Mehta, Kathleen McAvoy, Liam Evans, Marina Lyon and Manuel Rico Silvestre. Additional authors include Ruilin Yu, Connor Beveridge, Caitlin Randolph, Sanjay Iyer, Matheus Victor, Noelle Leary, Michael Steinbaugh, Zon Weng Lai, Giorgia Tosoni, Dilara Ayyildiz, Shannan Ho Sui, Kei Yamamoto, Makoto Murakami, Evgenia Salta, Li-Huei Tsai and Gaurav Chopra.
Paper cited: Vicidomini, C. et al. "An aging-sensitive secreted phospholipase confers neuroprotection and cognitive resilience." Nature Neuroscience. DOI: https://www.nature.com/articles/s41593-026-02465-z
Funding: This paper was supported by Simons Collaboration on Plasticity and the Aging Brain (AN-NC-AB-Research-00811243).
Disclosures: Sahay and Vicidomini are named co-inventors on U.S. patent PCT/US2023/01690, vectors and methods for the treatment of neurodegeneration, delaying cognitive decline and improving memory.
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