There is abundant evidence supporting the role of caspases in the development of neurodegenerative disease,
including Alzheimer’s disease (AD). Therefore, regulating the activity of caspases has been considered as a therapeutic
target. However, all the efforts on AD therapy using pan-caspase inhibitors have failed because of uncontrolled adverse
effects. Alternatively, the specific knockdown of caspase-3 gene through RNA interference (RNAi) could serve as a future
potential therapeutic strategy. The aim of the present study is to down-regulate the expression of caspase-3 gene using
lentiviral vector-mediated caspase-3 short hairpin RNA (LV-Caspase-3 shRNA). The effect of LV-Caspase-3 shRNA on
apoptosis induced by aluminum (Al) was investigated in primary cultured cortical neurons and validated in C57BL/6J
mice. The results indicated an increase in apoptosis and caspase-3 expression in primary cultured neurons and the cortex
ofmice exposed to Al, which could be down-regulated by LV-Caspase-3 shRNA. Furthermore, LV-Caspase-3 shRNA reduced
neural cell death and improved learning and memory in C57BL/6J mice treated with Al. Our results suggest that
LV-caspase-3 shRNA is a potential therapeutic agent to prevent neurodegeneration and cognitive dysfunction in aluminum-
exposed animal models. The findings provide a rational gene therapy strategy for AD.
Keywords: Apoptosis, Alzheimer’s disease, caspase-3, lentiviral vector-mediated caspase-3 shRNA, RNA interference.
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