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

Tauopathies, including Alzheimers 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 5GluCTC and 5GlyGCC tRFs induce Tau S396 phosphorylation, oligomerization, and impact neurite growth. Moreover, 5GluCTC is enriched in pathological Tau precipitates and co-localizes with oligomeric Tau in PS19 mouse brains. Inhibiting 5GluCTC 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 5GluCTC as a key regulator of Tau aggregation and suggest its inhibition as a promising therapeutic strategy for tauopathies. HighlightsO_LISpecific stress-induced 5tRFs strongly accumulate in Alzheimers disease brains C_LIO_LI5GluCTC binds and co-localizes to pathologic Tau in neurons and in the brain C_LIO_LI5GluCTC promotes Tau pathology while its inhibition reverses these effects C_LIO_LISpecific 5tRFs are horizontally transferred between neurons C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/725757v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@17e3d7borg.highwire.dtl.DTLVardef@f672b3org.highwire.dtl.DTLVardef@1e46716org.highwire.dtl.DTLVardef@2c10cb_HPS_FORMAT_FIGEXP M_FIG C_FIG