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

A novel Tau11i isoform was previously found to be enriched in Alzheimer’s disease (AD) brains. Further characterization showed that the 19-amino acid peptide encoded by retained intron 11 facilitates the formation of high-molecular-weight heterodimers and phase-separated liquid droplets, as well as enhances heparin-induced ?-sheet aggregation and cellular seeding of Tau11i. Compared to full-length Tau441 isoform, expression of Tau11i in human neurons caused significant transcriptional changes that recapitulated single-cell molecular signatures of neurofibrillary tangle (NFT)-free excitatory AD neurons in the prefrontal cortex. Additionally, Tau11i-expressing neurons showed dysregulated levels of specific ribosomal proteins and p21. Unlike Tau441, Tau11i interacts with Pinin and Poly(A)-binding protein Cytoplasmic 1 (PABPC1) in cells lacking AD pathology, mimicking the sequestration of RNA-binding proteins (RBP) by pathological Tau in AD brains. Notably, PABPC1 colocalizes with Tau11i in AD temporal lobes and is enriched at the 3’ untranslated regions of genes upregulated in Tau11i-expressing neurons. These findings suggest that Tau11i contribute to AD pathology by inducing neuronal senescence, pathological aggregation of RBPs, and transcriptional dysregulation that resembles the molecular signatures of NFT-free AD neurons.