Disorders of the Nervous System
Author: Carolina Lucía Facal | email: carolinaluciafacal@gmail.com
Carolina Lucía Facal 1°, Javier Andrés Muñiz 1°, A. Ezequiel Pereyra 1°, Ramiro Clerici Delville 1°, Indiana Páez Paz 1°, Mariano Soiza Reilly 2°, Germán Falasco 3°, Ana Damianich 1°, María Elena Avale 1°
1° Instituto de Investigaciones en Ingeniería Genética y Biología Molecular “Dr. Héctor N. Torres” (INGEBI – CONICET)
2° Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE – CONICET)
3° Laboratorio de Imágenes Moleculares, FLENI
Tauopathies are neurodegenerative diseases characterized by intraneuronal accumulation of hyperphosphorilated Tau protein, leading to neuronal dysfunction and neurodegeneration. Recent evidence suggests selective vulnerability of specific brain nuclei to initiate Tau pathology, from where pathological Tau propagates to other areas. Therefore, we aimed to validate a novel strategy for local Tau knock-down into specific brain nuclei in a mouse model of tauopathy. We analyzed the hTau mouse model of tauopathy, which primarily accumulates hyperphosphorylated Tau in the prefrontal cortex (PFC) and develops cognitive impairments and cortical-pyramidal neuronal firing deficits from 6 months-old. Artificial microRNAs designed to target the MAPT transcript were delivered into the PFC of hTau mice by lentiviral vectors, either before (3 months-old) or after (6 months-old) phenotypic onset. microRNAs efficiently reduced endogenous Tau in vivo by 50% in the PFC. Tau knock-down from 3 months-old prevented Tau pathology and cognitive impairments. Phenotypic rescue was also observed when microRNAs were administered at mid-stage (6 months-old) of Tau pathology onset. No adverse effects were observed neither in hTau nor wild type mice after microRNAs administration. Our results provide proof of concept for the potential use of microRNAs to locally reduce pathological Tau accumulation as a therapeutic approach for tauopathies.