Abstract
In Alzheimer disease, increased beta-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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism*
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Alzheimer Disease / pathology
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Amyloid Precursor Protein Secretases
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism
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Analysis of Variance
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Animals
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Aspartic Acid Endopeptidases
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Brain / drug effects
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Brain / metabolism
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Brain / pathology
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Brain / virology
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Cell Line
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Cloning, Molecular
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Disease Models, Animal
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Endopeptidases / chemistry
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Endopeptidases / genetics*
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Endopeptidases / metabolism*
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Genetic Vectors / physiology
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Glial Fibrillary Acidic Protein / metabolism
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Humans
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Immunohistochemistry / methods
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Lentivirus / physiology
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Maze Learning / drug effects
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Maze Learning / physiology
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Mice
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Mice, Transgenic
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Microtubule-Associated Proteins / metabolism
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Molecular Sequence Data
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RNA, Small Interfering / therapeutic use*
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Spatial Behavior / drug effects
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Time Factors
Substances
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Amyloid beta-Protein Precursor
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Glial Fibrillary Acidic Protein
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Microtubule-Associated Proteins
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Mtap2 protein, mouse
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RNA, Small Interfering
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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Bace1 protein, mouse