Stem Cell Enzyme PLA2G7 Emerges as a Driver of Age-Related Memory Decline

Deep inside the hippocampus, a thin layer of neural stem cells keeps working long after the brain finishes developing, and scientists have long suspected that these cells do far more than simply produce new neurons. A study published in Nature Aging now assigns them a strikingly direct role in the erosion of memory that accompanies aging. A team led by Fuling Wu, Yingxue Wu and Nannan Guo at Southern Medical University, working with Amar Sahay of Harvard Medical School, reports that a single secreted enzyme made by hippocampal stem cells, phospholipase A2 group VII, or PLA2G7, actively weakens the inhibitory wiring of the dentate gyrus. When the researchers silenced the gene encoding this enzyme in aged mice, inhibitory synapses rebounded, the balance of excitation and inhibition partially normalized, and the animals performed markedly better on demanding tests of spatial learning and memory.

The dentate gyrus is the hippocampal gateway through which information about new experiences must pass, and its circuit logic depends on a precise ratio of excitatory drive to inhibitory restraint. Granule cells, the principal neurons of the region, receive powerful excitatory inputs from the entorhinal cortex, but their output is sculpted by feedforward and feedback inhibition, much of it delivered by fast-spiking parvalbumin-positive interneurons. This inhibitory scaffold allows the dentate gyrus to perform pattern separation, the computational trick of making similar memories dissimilar, which is why subtle deficits in inhibition are thought to contribute to age-related forgetfulness. Previous work in aged rodents had already linked cognitive impairment to a shift in the excitation-inhibition ratio, but the molecular signals that push this balance astray remained elusive.

To find such a signal, the team turned to the neural stem cells themselves. These cells, which in the adult hippocampus largely persist as quiescent astrocyte-like radial glia, are known to secrete factors that shape their local niche, from PTN, which supports newborn neuron maturation, to vascular endothelial growth factor, which protects hippocampal vasculature. By mining transcriptomic datasets and validating expression in tissue, the researchers found that PLA2G7, an enzyme better known in cardiology as lipoprotein-associated phospholipase A2, is made by a substantial fraction of hippocampal stem cells and that its expression rises with age. In two-month-old mice, roughly 56 percent of Nestin-positive stem cells were PLA2G7-positive; by fourteen months that figure had climbed to nearly 72 percent, even as the total stem cell pool shrank by half.

The functional experiments hinged on conditional genetics. Using a Gli1-driven tamoxifen inducible system, the team deleted Pla2g7 specifically in neural stem cells and then examined the inhibitory terminals that contact dentate granule cells. The result was counterintuitive at first glance: removing a stem cell product increased inhibitory synapses. Markers of inhibitory boutons, including GAD67, gephyrin and the vesicle protein SYT2, rose substantially around granule cells in the knockout animals, while excitatory markers such as VGLUT2 were unchanged. Electrophysiology confirmed the anatomical shift, with spontaneous inhibitory postsynaptic currents becoming more frequent in granule cells lacking stem cell PLA2G7. The enzyme, in other words, acts as a brake on inhibitory circuit construction, and releasing that brake selectively strengthens inhibition.

Importantly, the effect could not be explained by changes in neurogenesis. Deleting Pla2g7 did not alter the number of stem cells, their activation state measured by MCM2 staining, or the production of doublecortin-positive immature neurons. Nor did it affect astrocyte numbers or the size and abundance of parvalbumin interneurons themselves. The authors also showed that deleting the gene in astrocytes, which express PLA2G7 even more broadly than stem cells, produced no measurable change in inhibitory puncta or spatial memory, pinpointing the stem cell population as the relevant source of the signal. Recombinant PLA2G7 protein applied to neuronal cultures reduced inhibitory synapse markers without harming cell viability, indicating a direct action of the secreted enzyme on synaptic architecture.

Because PLA2G7 is a lipid-metabolizing phospholipase, the team next asked what the enzyme does to the chemical environment of the hippocampus. Lipidomic profiling of dentate tissue from knockout and control mice revealed a broad remodeling of phospholipid composition, with numerous species of phosphatidylcholine, phosphatidylethanolamine and triglycerides differing between the groups. Many of the altered phosphatidylcholines carried docosahexaenoic acid, an omega-3 fatty acid abundant in synaptic membranes, and the abundance of specific lipid species correlated with performance in the active place avoidance task, a hippocampus-dependent behavioral assay. The findings place stem cell-derived lipid metabolism squarely within the growing literature connecting membrane lipids, synaptic vesicle cycling and neuronal excitability.

The lipid connection suggested a straightforward intervention. When the researchers supplemented cultures with a phosphatidylcholine preparation, the loss of inhibitory synapse markers normally caused by recombinant PLA2G7 was rescued, implying that the enzyme depletes substrates that inhibitory synapses need or generates products that suppress them. Whether dietary or pharmacological phosphatidylcholine could achieve the same rescue in living animals remains an open question, but the in vitro result provides a mechanistic handle and hints at a possible translational route that does not require gene therapy.

The most consequential experiments involved aged animals. In seventeen-month-old mice, the team injected lentiviruses carrying shRNAs against Pla2g7 directly into the dentate gyrus. Knockdown restored the density of SYT2-positive inhibitory puncta toward youthful levels and, in patch-clamp recordings, increased the frequency of spontaneous inhibitory currents and strengthened evoked inhibitory responses, while leaving excitatory transmission largely intact. Critically, the excitation-inhibition ratio, which rises steeply with age in this circuit, was partially normalized. Behaviorally, the treated aged mice improved on the novel object location task, learned to avoid a shock zone in the rotating arena more efficiently, and discriminated between similar contexts in fear conditioning tests more effectively than aged controls. Young animals, whose inhibitory circuits are already robust, gained little from the manipulation, suggesting the enzyme matters most when inhibition has begun to fail.

The study reframes adult neural stem cells as endocrine-like residents of the hippocampal niche whose secreted lipid signals can reshape circuit function independently of new neuron production, and it elevates PLA2G7, long tracked as a cardiovascular and inflammatory biomarker, into a candidate drug target for cognitive aging. Considerable caveats remain before human applications can be contemplated: the work was done in mice, the genetic and viral manipulations are far from clinically practical, and systemic PLA2G7 inhibition carries known cardiovascular considerations that would demand careful separation of peripheral and central effects. Nonetheless, the demonstration that silencing a single stem cell enzyme in the aged hippocampus can restore inhibitory synapses, rebalance a memory-critical circuit and improve learning offers a compelling new entry point into one of neuroscience’s most stubborn problems, and it predicts that the molecular conversation between stem cells and mature neurons will yield further surprises as the brain grows old.

Subject of Research: The role of the neural stem cell secreted enzyme PLA2G7 in regulating inhibitory synaptic circuits and cognitive aging in the mouse dentate gyrus

Article Title: Suppressing neural stem cell PLA2G7 restores inhibitory circuit function and improves cognition in aging mice

Article References: Suppressing neural stem cell PLA2G7 restores inhibitory circuit function and improves cognition in aging mice. (n.d.). https://doi.org/10.1038/s43587-026-01202-2

Image Credits: AI Generated

DOI: 10.1038/s43587-026-01202-2

Keywords: PLA2G7, neural stem cells, dentate gyrus, inhibitory synapses, hippocampus, cognitive aging, phosphatidylcholine, lipid metabolism, excitation-inhibition balance, spatial memory, Nature Aging, neurogenesis