Tau-mediated Disruption of the Spliceosome Triggers Cryptic RNA-splicing and Neurodegeneration in Alzheimer’s Disease

In Alzheimers disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal core components. In Drosophila models, pan-neuronal Tau expression triggers reductions in core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss-of-function in SmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA-sequencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle pathologic burden. Our results implicate spliceosome disruption and perturbations of the neuronal transcriptome in Tau-mediated neurodegeneration in AD.