183 | Neuronal cyto-specific lentivectors: A new tool for the analysis of selective vulnerability in tauopathies

Disorders of the Nervous System

Author: Clara Gaguine | Email: claragaguine@gmail.com

Clara Gaguine , Indiana de María Páez Paz , María Elena Avale


Tauopathies are neurodegenerative diseases associated with the abnormal metabolism of Tau protein, which leads to neuronal dysfunction and dementia symptoms. While Tau downregulation is a promising therapeutic strategy, global tau reduction might lead to undesired effects. Hence, developing more precise tools for Tau reduction only in affected neurons will enhance therapy efficiency and safety.
Two fundamental characteristics of Tauopathies are “selective neuronal vulnerability” and “selective regional vulnerability”, which indicate that the pathology affects specific neuronal types, and progressively impacts certain brain regions in a stereotyped and predictable manner.
The general aim of this project is focused on understanding the mechanisms underlying selective vulnerability due to the post-transcriptional regulation of Tau. We aim to express effective Tau-reducing microRNAs (Facal et al., 2023), but in a cyto- site specific manner.
We constructed lentiviral vectors (LVs) to achieve expression restricted to glutamatergic vs. GABAergic neurons, using engineered promoters for glutamatergic (CamKII) or GABAergic neurons (GAD67/h56D). LVs carrying reporter genes were stereotactically injected into the mouse prefrontal cortex to analyze the expression in the injected areas.
Further studies will involve specific expression of anti-Tau miRNAs in cultured human neurons and in a mouse model of tauopathy, to determine the outcomes of locally restricted tau downregulation.