Work

81. Hippocampal Gene Knockdown of BACE1 by Lentiviral Gene Transfer of siRNA Reduces Amyloid Pathology and Improves Memory Performance in APP Transgenic Mice

Year: 2006

Type: article

Abstract: The neurodegenerative process in Alzheimer's disease (AD) is associated with increased |[beta]|-secretase (BACE1) activity that results in progressive accumulation of amyloid precursor protein (APP) Cterminal fragments (CTFs) and amyloid-|[beta]| (A|[beta]|). Therefore, developing strategies to inactivate BACE1 might present an important approach toward the treatment of AD. To assess this possibility in vivo, APP transgenic mice that develop some aspects of AD neuropathology were treated with a lentiviral vector (LV) expressing small interfering RNA (siRNA) targeting BACE1. The LV-siBACE1 vector was expressed at high levels in HEK293T cells and reduced both BACE1 expression and production of A|[beta]|1-42 in vitro. Onemonth post intra-hippocampal delivery of the LV-siBACE1 vector in APP transgenic mice, levels of BACE1 expression were significantly reduced at the site of the injection. This was accompanied by reduced deposition of A|[beta]|, reduced intracellular CTFs and amelioration of the neurodegenerative alterations (dendritic / synaptic density) in the hippocampus as evaluated by confocal microscopy. Furthermore, the neuroprotective effects of LVsiBACE1 were associated with improved spatial learning and memory, tested by a Morris water maze. Our results suggest that lentiviral vector delivery of BACE1 siRNA can specifically reduce the cleavage rate of APP and neurodegeneration in vivo and indicates the potential therapeutic value of this approach for treating AD. We will discuss the possible outcome of long-term siRNA expression on the progression of AD in APP mice.

Source: Molecular Therapy

DOI: 10.1016/j.ymthe.2006.08.099