ENT1 inhibition links oligodendrocyte lipid metabolism to connectivity in tauopathy.

INTRODUCTION: Metabolic dysfunction, altered adenosine signaling, and white matter abnormalities are implicated in tauopathies, but their relationship to network disconnection remains unclear. Myelinating oligodendrocytes may represent a metabolically vulnerable hub linking these processes to circuit dysfunction. METHODS: We assessed human hippocampal tissue by immunofluorescence and profiled THY-Tau22 mice using diffusion tensor imaging, metabolomics, lipidomics, and single-nucleus RNA sequencing. Symptomatic mice were treated with the equilibrative nucleoside transporter 1 (ENT1) inhibitor J4 to evaluate therapeutic modulation. RESULTS: Hippocampal tissue from patients with tauopathy showed reduced oligodendrocyte- and myelin-associated CNPase signal. THY-Tau22 mice exhibited progressive reductions in hippocampal-prefrontal fractional anisotropy, myelin-associated alterations, purine and lipid metabolic remodeling, and oligodendrocyte-enriched lipid-associated transcriptional changes. J4 treatment selectively modulated purine and lipid metabolic pathways and improved myelin-associated markers and structural connectivity measures. DISCUSSION: ENT1 inhibition links adenosine homeostasis to oligodendrocyte-associated metabolic pathways and supports further investigation as a potential therapeutic approach for tauopathy-associated network dysfunction.