Boosting a protective gene helped aging mice preserve memory, suggesting that strengthening the brain’s own defenses could offer a way to delay cognitive decline in people.
Some older adults remain cognitively resilient even when their brains show signs of Alzheimer’s disease. Researchers investigating the biological mechanisms behind this resilience have identified a gene called Pla2g2f that may help protect the aging brain from memory loss.
In a study published in Nature Neuroscience, researchers found that increasing Pla2g2f activity in aging mice protected against synapse loss, inflammation, and disruptions in fat metabolism. Boosting the gene in middle-aged mice before substantial cognitive decline developed also changed the trajectory of age-related memory loss.
The study’s lead and senior authors are Cinzia Vicidomini, PhD, and Amar Sahay, PhD, respectively, of the Mass General Brigham Department of Psychiatry, the Harvard Stem Cell Institute, and the Broad Institute of Harvard and MIT.
Identifying the brain’s natural defenses against aging
As the brain ages, protective and harmful biological processes compete to influence its health. When harmful changes become dominant, synapses deteriorate, inflammation increases, and problems with lipid metabolism can interfere with normal brain function.
“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,” said Vicidomini.
To identify factors that might counteract these changes, the researchers searched for genes activated in response to synapse loss in the hippocampus, a brain region essential for memory. They focused on dentate granule cells, neurons involved in forming and processing memories.
Their investigation identified Pla2g2f, a gene that produces a secreted enzyme called a phospholipase. Its role in the brain had previously been unknown.
The researchers discovered that Pla2g2f levels increased in the hippocampus during aging and under conditions of brain inflammation. The gene was also expressed at higher levels in older adults whose brains showed signs of Alzheimer’s disease pathology but who remained cognitively resilient.
These findings suggested that Pla2g2f could be part of a natural protective response that helps the brain withstand age-related damage.
Boosting the gene protects memory in aging mice
To investigate the gene’s function, the team used genetic and viral tools to decrease or increase Pla2g2f activity in the brains of aging mice.
Reducing the gene’s activity worsened several features of brain aging, including synapse loss, inflammatory changes in microglia, increased reactivity in astrocytes, and impaired formation and maturation of new neurons. The mice also experienced disruptions in lipid metabolism, accumulation of fat droplets in brain cells, and greater memory impairment.
Increasing Pla2g2f activity had the opposite effect. It protected against many of these changes, helped maintain healthy communication between neurons, and preserved memory.
“Remarkably, boosting Pla2g2f in middle-aged mice before they developed substantial cognitive decline altered the trajectory of age-related memory loss,” said Sahay.
The results suggest that strengthening this protective mechanism before significant damage occurs may be especially valuable.
Reducing harmful fat buildup in brain immune cells
The researchers also uncovered a connection between Pla2g2f and the regulation of fats in the brain.
Microglia, the brain’s immune cells, help clear waste, maintain synapses, and support neurons. During aging and Alzheimer’s disease, however, these cells can accumulate lipid droplets, making them less effective and contributing to chronic inflammation.
Experiments using human microglia derived from induced pluripotent stem cells showed that neuronal PLA2G2F could influence these immune cells. Increasing its activity reduced the accumulation of lipid droplets and cholesterol esters, a form of stored cholesterol. Both are commonly found at elevated levels in microglia associated with Alzheimer’s disease.
Further experiments showed that disrupting the enzyme’s catalytic site prevented its ability to mobilize lipid droplets and reduce inflammatory changes in brain cells. This suggests that the enzyme’s biochemical activity is important for its protective effects.
Together, the findings point to PLA2G2F as a protective signal released by neurons that helps maintain healthy lipid metabolism and limit inflammation across brain cells.
Could this approach help prevent Alzheimer’s disease?
Aging is the greatest risk factor for Alzheimer’s disease, making the discovery of natural mechanisms that preserve memory particularly important.
The researchers believe that increasing Pla2g2f activity could eventually offer a way to strengthen cognitive resilience and potentially delay the onset of mild cognitive impairment or 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,” said Sahay.
However, the evidence for memory protection currently comes from animal experiments. Although the researchers also demonstrated beneficial effects in human microglia, it remains unknown whether increasing Pla2g2f activity would safely protect memory in people.
“Additional studies will be needed to determine whether this approach can be safely translated into therapies for patients,” Sahay said. “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.”
Reference: “An aging-sensitive secreted phospholipase confers neuroprotection and cognitive resilience” by 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 and Amar Sahay, 15 October 2026, Nature Neuroscience.
DOI: 10.1038/s41593-026-02465-z
This paper was supported by Simons Collaboration on Plasticity and the Aging Brain (AN-NC-AB-Research-00811243).
Disclosure: 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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