tRNA-derived fragments elevated in Alzheimer’s disease facilitate 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 induce Tau S396 phosphorylation, oligomerization, and impact neurite growth. Moreover, 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 stressed neurons and can be taken up by recipient cells, implicating them in the propagation of 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.