Regulation of tau isoforms relative contents restores cognitive deficits in a mouse model of tauopathy

FACAL, CAROLINA LUCIA; FERRARIO, JUAN ESTEBAN; DAMIANICH, ANA; MUNIZ, JAVIER; ESPINDOLA, SONIA; AVALE, MARIA ELENA

washington

Conferencia; Tau2020 Global Conference; 2020

Alzheimer's Association

Background: The alternative splicing of tau exon 10 gives rise to tau isoforms with either 3 or 4 microtubule binding repeats (3R or 4R). Equal amounts of these isoforms are produced in the normal adult human brain. In several tauopathies, as FTDP or PSP, that endogenous balance is altered. Modulation of tau isoforms could be a potential therapeutical approach, however, all the functional consequences are still unknown. Here we shifted tau contents in a preclinical model of tauopathy, the htau mice, which bears 3R>4R tau isoforms imbalance.Methods: Motor phenotypes were analyzed in the open field, grid test and rotarod; cognitive performance in the novel object recognition (NOR) task and anxiety levels in the elevated plus maze. Electrophysiological recordings were performed in living mice. microPET studies with FDG were used to determine changes in glucose metabolism. Finally, an RNA reprogramming strategy based on trans-splicing (TS) was used to modulate the 3R:4R tau isoforms. Stereotaxic injection of lentiviral vectors carrying TS molecules were performed in the prefrontal cortex or the striatum of htau mice. Behavioral phenotypic rescue was assessed 6 months after treatment and western blot and immunohistochemistry were performed to assess tau pathology.Results: Htau mice display motor impairments, cognitive deficits and behavioral disinhibition. FDG microPET analyses showed changes in glucose brain metabolism in the striatum and cortex of htau mice. However, hyperphosphorilated tau deposits were detected in the prefrontal cortex but not in the striata. By using the trans-splicing strategy we achieved an increase of 4R tau isoforms. Local modulation of tau isoforms in the prefrontal cortex improved cognitive deficit, restored neuronal firing patterns and reduced insoluble and hyperphosphorylated tau contents. In turn, shifting of 3R to 4R tau in the striatum improved motor coordination deficits in htau mice and rescued the normal firing of striatal neurons.Conclusions: Our results in the htau model evidence that tau 3R>4R imbalance leads to motor and cognitive impairments in mice. In addition, we demonstrated that the local modulation of tau isoforms is sufficient to preclude the development of pathological phenotypes, including behavioral deficits and neuronal firing.