56. Amelioration of Neurodegenerative and Neuropathological Alterations in a Transgenic Model of Alzheimer's Disease: Targeting BACE1 with Small Interfering RNAs

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) C-terminal 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 siRNAs 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. One month after the 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 amelioration of the neurodegenerative alterations in the hippocampus as evaluated by confocal microscopy in sections labeled with antibodies against dendritic and presynaptic markers and reduced deposition of amyloid and APPCTFs. 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. It will be interesting to see whether reduction in neurodegeneration in the hypocampus will result in improvement of cognitive functions.