140 | Targeted therapeutic strategy: Astrocyte-selective AAV-mediated IGF1 overexpression in the hippocampus to address sporadic Alzheimer’s Disease in a rat model

Cognition, Behavior, and Memory

Author: Facundo Peralta | Email: facundoperalta@med.unlp.edu.ar

Facundo Peralta , Ana Abril Vidal Escobedo , Juliette López Hanotte , María Florencia Zappa Villar , Paula Cecilia Reggiani , Joaquín Pardo

1° Instituto de Investigaciones Bioquímicas de La Plata “Prof. Dr. Rodolfo R. Brenner” (INIBIOLP-CONICET-UNLP)

Sporadic Alzheimer’s disease (sAD) is the most prevalent neurodegenerative disease. The cerebral histopathological study shows that the hippocampus (Hc) is severely damaged and presents marked reactive astrogliosis affecting neuronal function. We propose to use an astrocyte-targeted therapy mediated by bicistronic serotype 9 adeno-associated viruses (AAVs) driven by the gfaABC1D promoter (astrocyte-specific) overexpressing IGF1 using a sAD rat model mediated by the intracerebroventricular (icv) injection of streptozotocin (STZ). Methodology, young male rats were divided into 3 groups: SHAM, GFP and IGF1. On Experimental Day (ED) -28, animals received bilateral injections of artificial cerebrospinal fluid (aCSF)(SHAM), AAV-GFP (GFP), or AAV-IGF1 (IGF1), in Hc. On ED 0, animals received icv-aCSF (SHAM) or STZ (GFP/IGF1) (3mg/kg) bilaterally. Among ED +14/+25 behavioural tests were performed. Transgenes overexpression was confirmed by RT-qPCR and immunohistochemistry. GFP group showed significant impairment in exploratory and species-typical behaviour, recognition memory, spatial learning and memory, and a decrease in astrocyte complexity. IGF1 overexpression prevented STZ-induced changes in exploratory behaviour, learning and memory, and astrocyte complexity impairment (p<0.05). We explored a specific therapy that prevents the detrimental actions given by decreased astrocyte complexity, enhances their neuroprotection, and restores their modulatory properties in our sAD model.