렙틴유래 펩티드를 이용한 siRNA의 뇌전달 연구

Abstract

Aggregation of β-amyloid peptides in the brain is neurotoxic and occurs in Alzheimer’s disease (AD). This peptide is generated from the trans-membrane domain of the Amyloid Precursor Protein (APP) and the gamma-secretase enzyme that is involved in the generation of this peptide is considered an important physiological target to inhibit β-amyloid accumulation. Direct inhibition of gamma-secretase using inhibitors is known to cause severe side effects as notch protein is one of the substrates of the gamma-secretase. shRNA knockdown of the gamma secretase activating protein (GASP) results in significant reduction in the generation of β-amyloid peptides in vitro and in vivo without effecting the notch signaling pathway. Here, we developed a novel system for brain delivery of siRNA, a peptide that targets the leptin receptor expressed on neurons (Lep) was conjugated with NONA-arginine (9R) that complexes siRNA. Lep-9R delivered functional siRNA to different regions of the mouse brain when administered systemically, particularly the hippocampus which is the major region of β-amyloid accumulation in AD. IV treatment with Lep-9R complexed siGSAP biweekly for 8 weeks inhibited β-amyloid accumulation by reducing brain levels of GSAP in the 3xTg-AD mouse model of AD. Further the treatment also ameliorated AD behavior in this mouse model. Our results indicate that inhibiting β-amyloid accumulation through knockdown of GSAP results in reducing AD progression and that Leptin-9R can be used for the delivery of therapeutic siRNA for CNS-related diseases.