Abstract
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.
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This post is Copyright: | September 11, 2026
Neuro-Dementia