Local regulation of tau isoforms precludes motor and cognitive deficits in a mouse model of tauopathy

DAMIANICH, ANA; AVALE, MARIA ELENA; FERRARIO, JUAN ESTEBAN; ESPINDOLA, SONIA

Miami

Congreso; 3rd Pan American Parkinson?s Disease and Movement Disorders; 2020

Movement Disorders Society

Objectives: We aimed to validate a therapeutical intervention to preclude cognitive and motor deficits in a preclinical model of tauopathy, the htau mice, that bears an abnormal ratio of 3R:4R tau isoforms.Background: Tauopathies such as Frontotemporal dementia and Progressive Supranuclear Palsy (PSP) affect the basal ganglia thus leading to PD symptoms. In those pathologies the endogenous tau isoforms balance is frequently altered [1]. Modulation of tau isoforms is a potential therapeutical approach for those diseases. Methods: A gene therapy approach based on the trans-splicing RNA reprogramming strategy [2] was used to modulate the 3R:4R tau isoforms by estreotaxic injection of lentiviral vectors in the prefrontal cortex or the striatum of htau mice. Phenotypic rescue was assessed 6 months after treatment. Pathological phenotypes were analyzed in a battery of behavioral tests: Open field, grid test and rotarod were used to assess motor deficits. Cognitive performance was tested in the novel object recognition (NOR) task and anxiety levels in the elevated plus maze. Electrophysiological recordings in the striata of living mice were used to determine neuronal firing properties. Western blot and immunohistochemistry were performed to assess tau pathology as described [3]. Results: The htau model present an excess of 3R tau isoform in the brain associated with pathological phenotypes. Htau mice displayed motor impairments and cognitive deficits at 12 months old. In addition, behavioral disinhibition was observed in the elevated plus maze at 6 months old, before the onset of motor and cognitive signs. By using the trans-splicing strategy we successfully achieved normal levels of 4R tau isoforms in the injected areas of the htau brain. Moreover, 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, local shifting of 3R to 4R tau in the striatum also improved motor coordination deficits in htau mice and rescued the normal firing of striatal neurons.Conclusions: Our results in the htau model evidence that the consequences of tau 3R:4R imbalance include the development of motor and cognitive impairments, as observed in PSP and FTDP human tauopathies. 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. These results obtained using tau isoforms modulation in the htau model set the grounds for the potential use of RNA reprogramming to correct tau splicing defects in human tauopathies.1. Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12:609?622. doi: 10.1016/S1474-4422(13)70090-52. Avale ME, Rodríguez-Martín T, Gallo JM (2013) Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing. Hum Mol Genet 22:2603?2611. doi: 10.1093/hmg/ddt1083. Espindola S, Damianich A, Sartor M, Alvarez R., Belforte J.E., Ferrario J.E., Gallo J.M., Avale M.E. 2018. Modulation of tau isoforms imbalance precludes tau pathology and cognitive decline in a mouse model of tauopathy. Cell Reports 2018. 23(3):709-715. doi: 10.1016/j.