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Modulation of Tau Isoforms Imbalance Precludes Tau Pathology and Cognitive Decline in a Mouse Model of Tauopathy

Research output: Contribution to journalArticle

Sonia Lorena Espíndola, Ana Damianich, Rodrigo Javier Alvarez, Manuela Sartor, Juan Emilio Belforte, Juan Esteban Ferrario, Jean-Marc Gallo, María Elena Avale

Original languageEnglish
Pages (from-to)709-715
Number of pages7
JournalCell Reports
Volume23
Issue number3
Early online date17 Apr 2018
DOIs
Accepted/In press16 Mar 2018
E-pub ahead of print17 Apr 2018
PublishedApr 2018

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Abstract

Summary

The microtubule-associated protein tau regulates myriad neuronal functions, such as microtubule dynamics, axonal transport and neurite outgrowth. Tauopathies are neurodegenerative disorders characterized by the abnormal metabolism of tau, which accumulates as insoluble neuronal deposits. The adult human brain contains equal amounts of tau isoforms with three (3R) or four (4R) repeats of microtubule-binding domains, derived from the alternative splicing of exon 10 (E10) in the tau transcript. Several tauopathies are associated with imbalances of tau isoforms, due to splicing deficits. Here, we used a trans-splicing strategy to shift the inclusion of E10 in a mouse model of tauopathy that produces abnormal excess of 3R tau. Modulating the 3R/4R ratio in the prefrontal cortex led to a significant reduction of pathological tau accumulation concomitant with improvement of neuronal firing and reduction of cognitive impairments. Our results suggest promising potential for the use of RNA reprogramming in human neurodegenerative diseases.

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