PR002556 (Project)

Description:Ependymal cells (ECs) are specialized multi-ciliated glial cells that line the ventricular system of the brain, regulating cerebrospinal fluid flow (CSF) and the neighbouring neural stem cell (NSC) niche. However, their role in maintaining brain homeostasis or in disease pathogenesis remains unclear. To elucidate their function, we disrupted ependymal glucose metabolism by genetically deleting glucose-transporter-1 (GLUT1/Slc2a1) in postnatal ECs. Analyses were carried out across three separate studies (batches), with one study at 1 month (6 mice) and two studies at 12 months (3 mice, 5 mice). Results from this project confirm CSF flow changes and disrupted NSC differentiation and neuroblast migration. These mice also exhibited periventricular lipid droplet accumulation similar to Alzheimer’s disease brains. Aged cKO mice exhibited progressive cognitive and motor dysfunction, and onset of seizure activity. These behavioral deficits were coincident with various neurodegenerative pathologies, including dysmyelination, microglia-associated inflammation, and lipid imbalance. When combined with metabolic perturbation in ECs, 5xFAD mice exhibited accelerated disease onset. These findings suggest that ECs are important regulators of brain homeostasis, and their dysfunction may contribute to the pathogenesis of neurodegenerative diseases.