181 | Engineered Tau microRNAs modulate neuronal physiology and rescue tauopathy phenotypes in a preclinical model

Disorders of the Nervous System

Author: Carolina Lucía Facal | Email: carolinaluciafacal@gmail.com

Carolina Lucía Facal , Iván Fernández-Bessone , Javier Andrés Muñiz , A. Ezequiel Pereyra , Olivia Pedroncini , Cayetana Arnaiz , Ramiro Clerici-Delville , Indiana Páez-Paz , Leandro Urrutia , Germán Falasco

1° Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI-CONICET)
2° Instituto de Biología Celular y Neurociencias (IBCN-UBA-CONICET)
3° Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA-CONICET-MPSP)
4° Centro de Imágenes Moleculares (FLENI)

Abnormal protein tau accumulation is the hallmark of several neurodegenerative diseases, named tauopathies. Strategies directed to reduce tau in the brain are promising for therapeutic intervention, yet, development of long-term treatments needs optimization, and better understating of the functional pathways potentially affected by tau reduction. Here we developed artificial microRNAs targeting the human MAPT mRNA to dwindle tau protein synthesis. In human differentiated neurons in culture, microRNAs-directed tau reduction decreased neuronal firing but did not affect neuronal morphology nor impaired axonal transport. In turn, in the htau mouse model of tauopathy, microRNA expression into the medial prefrontal cortex prevented pathological tau accumulation, modulated firing activity of putative pyramidal neurons, and improved glucose uptake in PET scans. Moreover, local tau knockdown prevented cognitive decline in aged htau mice. Our results demonstrate target engagement of designed tau-microRNAs and provide proof of concept for their therapeutic benefit to rescue tauopathy-related phenotypes.