Diabetes increases SCO-spondin secretion but reduces Wnt5a interaction with ependymal cells, inducing ciliary stiffness and Frizzled-2 downregulation.

Diabetes is a chronic metabolic disorder with systemic complications. Hyperglycemia damages multiple organs, including the brain, increasing the risks of stroke, dementia, and oxidative stress. Diabetes is also linked to ventricular enlargement in the human brain. Here, we examine how diabetes alters the secretion of subcommissural organ spondin (SCO-spondin) and Wnt5a by SCO cells, which subsequently affects ependymal ciliary beating and cerebrospinal fluid (CSF) circulation. Under diabetic conditions, SCO-spondin secretion by SCO cells increased. CSF-borne SCO-spondin was observed interacting with ependymal cilia, which showed increased stiffness. Control SCO cells were Wnt5a-positive, indicating active biosynthesis and secretion; in contrast, Wnt5a immunostaining was negative under diabetic conditions, and its interaction with ependymal cells decreased. Additionally, the Wnt5a receptor Frizzled-2 and the proteoglycan testican, essential for Wnt5a-receptor engagement, were not detected in ependymal cells during diabetes. To further explore downstream changes, we examined aquaporin-4 (AQP4) in control and diabetic samples and found condition-dependent differences in its subcellular distribution within ependymal cells. Accordingly, peri-ependymal edema and periventricular lucency were observed. Conversely, GLUT1, MCT2, and Cx-43 remained unchanged, suggesting that diabetes selectively modifies specific ependymal properties. Proteomic analysis of CSF from diabetic patients confirmed the presence of spondin-1 and thrombospondins, which may replace SCO-spondin in humans. Overall, these findings support a model where increased SCO-spondin release and decreased Wnt5a-Frizzled-2-testican signaling in ependymal cells promote ciliary stiffening and periventricular edema in the diabetic brain.