Modulation of Tau isoforms by RNA reprogramming: phenotypic recovery in a mouse model of Tauopathy

ESPINDOLA, SONIA L.; DAMIANICH, ANA; BLANK, ZOE; AVALE, M. ELENA

Rio de Janeiro

Congreso; IBRO - 9th World Congress International Brain Research Organization; 2015

International Brain Research Organization (IBRO)

Tauopathies are major neurodegenerative diseases characterized by the presence of intraneuronal aggregates of the protein Tau in insoluble neurofibrillary tangles. Tau is a microtubule-associated protein predominantly expressed in neurons, involved in many cellular functions such as microtubule stabilization and axonal transport. Human Tau is encoded by the MAPT gene, which comprises 16 exons. The Exon 10 can be alternatively spliced, giving rise to Tau isoforms with three (3R) or four (4R) repeats of microtubule binding domains; both isoforms are expressed in equal amounts in the normal adult human brain. Several tauopathies are associated with mutations in the MAPT gene which modify E10 alternative splicing, leading to an imbalance between the 3R and 4R Tau isoforms, disrupting the normal ratio. Correction of that imbalance might represent a therapeutical approach for those tauopathies. In this work we evaluate the phenotypes of mice carrying a human Tau transgene with an abnormal ratio of Tau isoforms (hTau mice), proposed as a model of tauopathy. Htau mice have an excess of 3R Tau in several brain areas. We use RNA reprogramming to modulate the Tau 4R/3R ratio in vivo and analyse if such restoration produces a phenotypic rescue. We delivered a RNA pre-trans-splicing molecule (PTM) to create a chimeric mRNA through a trans-splicing reaction to promote the inclusion of Exon 10. PTMs were delivered into the adult mouse brain by lentiviral vectors. Cognitive performance was tested in the novel object recognition task and the Morris Water Maze. Tau isoforms content was determined by qPCR and Western blot. The presence of Tau aggregates was analysed in several brain areas by immunohistochemistry, while the difference between soluble and insoluble forms of Tau was analyzed by western blot. Htau mice rescued by trans-splicing restored some cognitive and neurochemical phenotypes, indicating that RNA reprogramming is a suitable tool to achieve a relevant phenotypic recovery in this model of tauopathy. Our results raise promising perspectives about using RNA reprogramming to treat human tauopathies related to tau isoforms imbalance.