Modulation of Tau 3R:4R Isoforms Imbalance Precludes Motor and Cognitive Impairments in a Mouse Model of Tauopathy

LIC. ANA DAMIANICH; CAROLINA LUCIA FACAL; LIC. SONIA L ESPINDOLA; DR. JEAN-MARC GALLO; DR. JUAN E FERRARIO; DRA. MARÍA ELENA AVALE

Londres

Simposio; PSP & CBD International Research Symposium 2018; 2018

PSP Association and Cure PSP

The microtubule associated protein tau is highly expressed in neurons and involved in microtubule dynamics and axonal transport. Alternative splicing of exon 10 (E10) in the primary transcript produces tau protein isoforms with 3 or 4 microtubule binding domains (3R and 4R). The human normal adult brain expresses equal amounts of both isoforms, while imbalances in 3R:4R relative contents are associated with several tauopa-thies, such as PSP.In this study we analyzed cognitive and motor phenotypes in the htau mouse model of tauopathy, which pro-duces abnormal content of human 3R:4R tau isoforms. These mice show severe impairments in motor coordi-nation (rotarod) and reduced cognitive performance (novel object recognition). Increased 3R tau contents were observed in the prefrontal cortex (PFC) and the striatum of htau mice, compared to WT mice that express only the 4R isoform, suggesting that the 3R>4R abnormal levels could underlie the observed phenotypes. We used a trans-splicing RNA reprogramming strategy to control the inclusion of E10 of the endogenous tau tran-script into the htau brain. Trans-splicing molecules were locally delivered by lentiviral vectors into the PFC or the striatum of adult hTau mice (3 months old). Effective rescue of tau isoforms imbalance was observed at the RNA and protein level. The trans-splicing treatment precluded cognitive impairment and motor deficits in senile htau mice. Moreover, local modulation of isoforms imbalance reduced insoluble and hyperphosphory-lated tau contents and restored normal neuronal firing.Our results suggest that cognitive and motor coordination impairments observed in htau mice are related to the abnormal 3R:4R tau isoforms content, rising this model as a suitable tool to evaluate therapeutic ap-proaches for tauopathies related to tau isoforms imbalance. In addition, we provide a proof of concept for the use of trans-splicing as a potential RNA-therapy strategy to modulate 4R:3R abnormal levels in the adult brain.