Translated retained intron 11 sequence confers pathological properties to Tau in Alzheimer’s disease

The pathological aggregation of Tau protein into oligomers and fibrils plays a central role in Alzheimer's disease (AD). Here, we explore the biochemical and cellular properties conferred by a unique 19-amino acid intronic peptide found exclusively in the Tau11i isoform. We demonstrate that this intronic peptide mediates robust formation of high molecular weight (HMW) oligomers that resist denaturing and reducing conditions, distinguishing Tau11i from other Tau isoforms lacking this sequence. Tau11i also uniquely forms stable heterodimers with Tau441, suggesting a role in the propagation of Tau pathology. Additionally, the intronic peptide enhances Tau11i’s liquid-liquid phase separation (LLPS), a critical early event associated with pathological aggregation. In vitro assays showed that Tau11i aggregates into β-sheet-rich fibrils more efficiently than other Tau isoforms, significantly facilitating fibril formation and cellular seeding in Tau biosensor cells. Transcriptomic profiling indicated substantial dysregulation in neuronal pathways involving immune response, synaptic function, and metabolism, with Tau11i-expressing neurons closely mirroring the gene expression patterns of AD neurons, particularly the AT8-negative subtype. Furthermore, Tau11i specifically interacts with stress granule-associated RNA-binding proteins, notably PABPC1, implicating it in stress granule dynamics and RNA homeostasis. Collectively, these findings identify the intronic peptide as a critical factor driving Tau11i-specific oligomerization and early-stage molecular alterations associated with Alzheimer's disease, highlighting its potential as a novel therapeutic target distinct from classic Tau pathology.