Investigation of the effect of PGC1A gene therapy at advanced stages of Alzheimer’s disease in an animal model of amyloid pathology

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent form of dementia in the elderly. AD has no cure but symptomatic treatment, thus, an effective therapy is urgently needed. Previously in our laboratory we have explored the potential neuroprotective effects of the coactivator for the peroxisome proliferator‐activated receptor‐γ (PPARγ), ‐PGC‐1α mainly involved in the regulation of metabolic processes and mitochondrial biogenesis. PGC‐1α has been shown to be involved in different neurodegenerative diseases and its expression is reduced in the brain of AD patients. We have previously showed that the delivery of PGC‐1α through lentiviral vectors in APP23 mice, at the preclinical stage of the disease, resulted in reduction of amyloid‐β deposition, protection against neuronal loss and improvement of cognition functions. Therefore, the aim of this study was to generate a monocistronic lentiviral vector expressing PGC‐1α to investigate whether this therapy could ameliorate the cognitive deficit ofAPP23 mouse model of AD at an advanced stage of pathology.MethodA recombinant lentiviral vector carrying human codon optimized PGC‐1αdriven by CMV promoter was constructed and produced. To determine the therapeutic effects of overexpression of PGC‐1α, we delivered the lentiviral vector carrying PGC‐1α in the frontal cortex and hippocampus of wildtype and APP23 mice at 12 months old and animals were sacrificed 3 months later. We investigated locomotor activity and anxiety (Open Field, OF), non‐spatial (Novel Object Recognition, NOR) and spatial memories (Object Location test, OLT).ResultSo far, no differences were observed in the anxiety and locomotor activity between the groups in the OF test. APP23 mice at 15 months of age showed cognitive impairment compared with controls. Interestingly, improvement in the performance in the NOR test was observed in the APP23 mice injected with PGC‐1α vector (p>0.05, two‐way ANOVA, Bonferroni post‐hoc, n=5‐10 per group). However, in the OLT test no difference was observed between the groups 3 months after the PGC‐1α delivery.ConclusionThese preliminary results support the potential therapeutic effect of PGC1alpha on cognition at late stages of the disease.