Abstract
The degenerative process of Alzheimer's disease is linked to a shift in the balance between amyloid-beta (Abeta) production, clearance, and degradation. Neprilysin has recently been implicated as a major extracellular Abeta degrading enzyme in the brain. However, there has been no direct demonstration that neprilysin antagonizes the deposition of amyloid-beta in vivo. To address this issue, a lentiviral vector expressing human neprilysin (Lenti-Nep) was tested in transgenic mouse models of amyloidosis. We show that unilateral intracerebral injection of Lenti-Nep reduced amyloid-beta deposits by half relative to the untreated side. Furthermore, Lenti-Nep ameliorated neurodegenerative alterations in the frontal cortex and hippocampus of these transgenic mice. These data further support a role for neprilysin in regulating cerebral amyloid deposition and suggest that gene transfer approaches might have potential for the development of alternative therapies for Alzheimer's disease.
Publication types
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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 / genetics
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / genetics
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Amyloidosis / genetics*
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Amyloidosis / therapy*
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Animals
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Brain / drug effects
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Brain / metabolism
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Brain / pathology
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Cell Line
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Disease Models, Animal
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Drug Administration Routes
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Frontal Lobe / drug effects
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Frontal Lobe / metabolism
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Frontal Lobe / pathology
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Gene Transfer Techniques
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Genes, Reporter
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Genetic Therapy / methods*
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Genetic Vectors / administration & dosage
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Genetic Vectors / genetics
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Hippocampus / drug effects
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Hippocampus / metabolism
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Hippocampus / pathology
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Humans
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Kidney / cytology
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Kidney / metabolism
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Lentivirus / genetics
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Mice
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Mice, Transgenic
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Neprilysin / biosynthesis
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Neprilysin / genetics*
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Neprilysin / pharmacology*
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Peptide Fragments / metabolism
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Plaque, Amyloid / drug effects
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Plaque, Amyloid / pathology
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Stem Cells / metabolism
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Treatment Outcome
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Peptide Fragments
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amyloid beta-protein (1-42)
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Neprilysin