Cellular and Molecular Neurobiology
Author: Facundo Peralta | email: facundoperaltaunlp@gmail.com
Facundo Peralta 1°, Juliette López Hanotte 1°, Juan Ignacio Posada 1°, Tomas Björklund 2°, Paula Cecilia Reggiani 1°, Joaquín Pardo 1°2°
1° Biochemistry Research Institute of La Plata Professor Doctor Rodolfo R. Brenner (INIBIOLP) – School of Medical Sciences, National University of La Plata, Argentina.
2° Molecular Neuromodulation, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
Neuroinflammation is one of the hallmarks of neurodegenerative diseases (ND) characterized by reactive glial cells that undergo several morphological and transcriptional changes. The most prevalent age-related ND is sporadic Alzheimer’s disease (sAD), a condition in which the hippocampus (Hc) is severely affected and where astrocytes have been shown to become reactive, decreasing their neuronal trophic support. In this regard, gene therapy and the use of potent neurotrophic factors, such as Insulin-Like Growth Factor 1 (IGF1) and Glial Cell-Derived Neurotrophic Factor (GDNF), are emerging as promising therapeutic approaches. In a rat sAD model generated by intracerebroventricular (icv) injection of streptozotocin (STZ), we previously studied the morphologic changes of reactive astrocytes. In order to genetically modulate these cells in sAD rats and restore brain homeostasis, we constructed and characterized, in vivo, 3 bicistronic adeno-associated viral vectors that simultaneously overexpress in astrocytes the IGF1, GDNF or GFP genes followed by the TdTomato reporter gene. Vectors were injected in the Hc of adult rats and 3 weeks after injection, overexpression of the transgenes were confirmed by RT-qPCR. By fluorescence and immunohistochemistry, we observed that 97% of transduced cells were astrocytes. Next, we will assess the neuroprotective potential of preventive gene therapy with IGF1 and GDNF in hippocampal astrocytes of icv-STZ treated rats.