tRNA-derived fragments elevated in Alzheimer’s disease promote Tau aggregation

Summary Tauopathies, including Alzheimer’s disease (AD), are driven by pathological Tau aggregation, a process that requires co-factors. Small RNAs (sRNA) have been proposed as such co-factors, yet little is known about endogenous transcripts that promote Tau pathology. We identify stress-induced tRNA-derived RNAs or fragments (tDRs/tRFs) as the most dysregulated sRNA class in human AD brains, PS19 mice overexpressing mutant human Tau, and human neuronal tauopathy models. Notably, the highly accumulating 5’Glu CTC and 5’Gly GCC tRFs directly bind Tau and induce its phosphorylation, oligomerization, fibril formation, and impact neurite growth. 5’Glu CTC is enriched in pathological Tau precipitates and co-localizes with oligomeric Tau in PS19 mouse brains. Inhibiting 5’Glu CTC mitigates Tau pathology. Furthermore, these tRFs are highly secreted by neurons and can be taken up by recipient cells, contributing to Tau pathology. Our findings establish 5’Glu CTC as a key regulator of Tau aggregation and suggest its inhibition as a promising therapeutic strategy for tauopathies. Highlights Specific stress-induced 5’tRFs strongly accumulate in Alzheimer’s disease brains 5’Glu CTC binds and co-localizes with pathologic Tau in neurons and in the brain 5’Glu CTC promotes pathologic Tau species while its inhibition reverses these effects Specific 5’tRFs are horizontally transferred between neurons