A secreted enzyme produced by neurons in the hippocampus helps protect the aging mouse brain against synapse loss, inflammation and memory decline, according to a study published October 15, 2026 in Nature Neuroscience by researchers at Massachusetts General Hospital, the Harvard Stem Cell Institute and the Broad Institute. In mice, deleting the gene for the enzyme, called PLA2G2F, worsened age related loss of synapses, drove up inflammatory glial activity and impaired hippocampal dependent memory; raising the enzyme's levels in aged mice preserved synapses, reduced that inflammation and improved performance on spatial memory tests compared with unaltered animals of the same age.
The researchers identified PLA2G2F in a screen for genes activated in hippocampal dentate granule cells after synapse loss, then found its expression rises with age in that same mouse brain region. The enzyme is secreted and breaks down lipids on the outer surface of cell membranes into smaller fatty byproducts, which the authors propose help remodel synapses and calm inflammatory responses in surrounding brain tissue. In a separate mouse model bred to develop Alzheimer's like brain pathology, boosting the enzyme reduced amyloid burden and preserved hippocampal dependent memory, the authors reported. The team frames the enzyme as a distinct molecular candidate for the long theorized but largely unidentified compensatory mechanisms behind cognitive reserve, separate from previously studied resilience scores or microglia centered pathways.
The authors also looked at human tissue. Using published gene expression datasets, they found PLA2G2F activity rises with human brain age, and in postmortem brain samples from donors who had undergone cognitive testing before death, enzyme levels were highest in people who stayed cognitively intact despite carrying amyloid beta plaques, a hallmark of Alzheimer's disease, according to Nature's own news account of the paper. That human finding is observational: it comes from brain tissue examined after death, not from a clinical trial or an intervention, and it cannot by itself show that the enzyme caused the resilience the researchers observed.
Outside scientists described the approach favorably while flagging how far the work remains from any human application. Timothy Hohman, a neuroscientist and geneticist at the Vanderbilt Memory & Alzheimer's Center who was not involved in the study, called it a "fantastic, very thoughtful approach" to identifying what protects neurons during aging, Nature reported. The study's own authors say additional research is needed before any attempt to safely raise the enzyme in the aging human brain could be considered, and describe that work as still in early exploration.