SFRP1 drives glycolytic activation in astrocytes during neuroinflammation

Abstract

Astrocytes and microglia maintain brain homeostasis and respond to inflammation through functions coordinated by molecular mediators they produce. Growing evidence shows that cellular metabolism is key to how these cells adapt to challenges. However, little is known about what drives glial metabolic reprogramming or whether molecules involved in astrocyte- microglia crosstalk also regulate this process. Here, we explored this question focusing on Secreted Frizzled-Related Protein 1 (SFRP1). SFRP1 is an astrocyte-derived factor induced by inflammatory cues and overexpressed in neurodegeneration, which fosters microglial response to inflammation through NF-{kappa}B/HIF-dependent programs. We combined mitochondrial morphometry (MitoTracker Red and MiNA analysis) with Seahorse extracellular flux assays (Mito Stress Test) to determine whether SFRP1 modulates glial bioenergetics in primary cultures of astrocytes and microglia from wild-type and Sfrp1-/- mice. We report that SFRP1 acts as a driver of astrocytic metabolic activation, preferentially enhancing glycolysis over mitochondrial respiration. This effect is most pronounced during inflammation, when oxidative phosphorylation is restricted and SFRP1 enhances glycolytic flexibility to sustain energy demands. By contrast, microglia showed the expected LPS-driven glycolytic shift with minimal dependence on SFRP1 under monoculture conditions. These findings position SFRP1 as a candidate regulator of astrocyte-centered metabolic tuning during neuroinflammation, with implications for disorders such as Alzheimers disease, in which SFRP1 is elevated.