Nature Neuroscience
8, 1343 - 1349 (2005)
Published online: 28 August 2005; | doi:10.1038/nn1531
Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic modelOded Singer1, 4, Robert A Marr1, 4, Edward Rockenstein2, Leslie Crews2, Nicole G Coufal1, Fred H Gage1, Inder M Verma1
& Eliezer Masliah2, 31
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA. 2
Department of Neurosciences, The University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. 3
Department of Pathology, The University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to Eliezer Masliah emasliah@ucsd.edu or Inder M Verma verma@salk.edu In Alzheimer disease, increased  -secretase (BACE1) activity has been associated with neurodegeneration and accumulation of amyloid precursor protein (APP) products. Thus, inactivation of BACE1 could be important in the treatment of Alzheimer disease. In this study, we found that lowering BACE1 levels using lentiviral vectors expressing siRNAs targeting BACE1 reduced amyloid production and the neurodegenerative and behavioral deficits in APP transgenic mice, a model of Alzheimer disease. Our results suggest that lentiviral vector delivery of BACE1 siRNA can specifically reduce the cleavage of APP and neurodegeneration in vivo and indicate that this approach could have potential therapeutic value for treatment of Alzheimer disease.
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