Adeno-associated viral vectors overexpressing neurotrophic factors in hippocampal astrocytes as a potential therapeutic technology for neurodegenerative diseases

PERALTA FACUNDO; LÓPEZ HANOTTE JULIETTE; POSADA JUAN IGNACIO; BJÖRKLUND TOMAS; REGGIANI PAULA CECILIA*; PARDO JOAQUÍN*

Buenos Aires

Encuentro; SAN Meeting 2022; 2022

Sociedad Argentina de Investigaciones en Neurociencias

Neuroinflammation is one of the hallmarks of neurodegenerative diseases (ND)characterized by reactive glial cells that undergo several morphological andtranscriptional changes. The most prevalent age-related ND is sporadicAlzheimer´s disease (sAD), a condition in which the hippocampus (Hc) isseverely affected and where astrocytes have been shown to become reactive andin consequence, neuronal trophic support decreases. In this regard, gene therapyand the use of potent neurotrophic factors, such as Insulin-Like Growth Factor 1(IGF1) and Glial Cell-Derived Neurotrophic Factor (GDNF), are emerging aspromising therapeutic approaches. In a rat sAD model generated byintracerebroventricular (icv) injection of streptozotocin (STZ), we previouslystudied the morphologic changes of reactive astrocytes. In order to geneticallymodulate astrocytes in sAD rats and restore brain homeostasis, we constructedand characterized, in vivo, 3 bicistronic adeno-associated viral vectors thatsimultaneously overexpress the IGF1, GDNF or GFP genes followed by theTdTomato reporter gene, selectively in astrocytes. Vectors were injected in theHc of adult rats and 3 weeks after injection, we confirmed by RT-qPCRoverexpression of the transgenes. By fluorescence and immunohistochemistry,we observed that 97% of transduced cells were astrocytes. Next, we will assessthe neuroprotective potential of preventive gene therapy with IGF1 and GDNFin hippocampal astrocytes of icv-STZ treated rats.