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

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.