Targeted delivery of BACE1 siRNA for synergistic treatment of Alzheimer's disease

Background The deposition of toxic aggregated amyloid-β (Aβ) is a key pathogenic event in Alzheimer's disease (AD), resulted from the continuous cleavage of amyloid precursor protein (APP) by BACE1 (β-site APP cleaving enzyme 1) and γ-secretase. Small interfering RNA (siRNA) has shown great potential for disease treatment by specifically silencing target gene. However, the poor brain delivery efficiency of siRNA limits its therapeutic efficacy against AD. Methods Herein, this study designed a simplified while effective BACE1 siRNA (siBACE1) delivery system, namely dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1). Results PPR@siBACE1 could cross the blood brain barrier efficiently and enter brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment with PPR@siBACE1 not only curtails the production of Aβ but also potentiates the phagocytosis of Aβ by microglia, with much improvement of the memory deficit and reduced neuroinflammatory response in AD mice. Conclusions In summary, this study provides a reliable delivery platform for the gene therapy of AD.