ENT1 inhibition links oligodendrocyte lipid metabolism to connectivity in tauopathy

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.

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.

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.

ENT1 inhibition links adenosine homeostasis to oligodendrocyte-associated metabolic pathways and supports further investigation as a potential therapeutic approach for tauopathy-associated network dysfunction.