176 | Downregulation of the Fyn kinase in an experimental model of tauopathy: functional consequences and therapeutic perspectives

Disorders of the Nervous System

Author: Ramiro Clerici Delville | Email: ramiroclerici@hotmail.com

Ramiro Clerici Delville , Javier Andrés Muñiz , Carolina Lucía Facal , Ezequiel Pereira , Melina Bordone , Juan Esteban Ferrario , Maria Elena Avale

1° Instituto de Investigaciones en Ingeniería Genética y Biología Molecular “Dr. Héctor N. Torres” (INGEBI-CONICET)
2° Instituto de Biociencias, Biotecnología y Biología traslacional (iB3 – FCEN – UBA)

Tauopathies are neurodegenerative diseases, showing accumulation of hyperphosphorylated Tau. Tau is a microtubule-associated protein, predominantly expressed in neurons, involved in many neuronal processes. In many tauopathies, Tau becomes abnormally hyperphosphorylated at specific sites, reducing its affinity for axonal microtubules and promoting its accumulation in the somatodendritic compartment. The src-Fyn kinase has been characterized as a crucial mediator of Tau-dependent neurodegeneration, and it is hypothesized that Tau-Fyn interaction is required for Tau toxicity. This interaction is enhanced in pathologic conditions, favoring the overstimulation of glutamatergic receptors, which generates what is known as “excitotoxicity”. Here we analyzed the interaction between Tau and Fyn, in the development of Tau pathology in the hTau mouse model of tauopathy, which primarily accumulates phospho-Tau in the prefrontal cortex (PFC) and develop cognitive impairments from 6 months-old. We performed specific downregulation of Fyn in the PFC of 3-months-old hTau mice, by stereotaxic injections of lentiviral vectors carrying microRNAs to target Fyn mRNA. Six months after treatment, mice were analyzed using a battery of behavioral tests, in vivo electrophysiological recordings of PFC neurons and molecular-post mortem analyses. We determined whether Fyn downregulation has a beneficial impact on neuronal physiology and phenotypic impairments in aged hTau mice.