Neprilysin Gene Transfer Reduces Human Amyloid Pathology in Transgenic Mice

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 demons...

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Bibliographic Details
Published in:The Journal of neuroscience 2003-03, Vol.23 (6), p.1992-1996
Main Authors: Marr, Robert A, Rockenstein, Edward, Mukherjee, Atish, Kindy, Mark S, Hersh, Louis B, Gage, Fred H, Verma, Inder M, Masliah, Eliezer
Format: Article
Language:English
Subjects:
Alzheimer Disease - genetics
Amyloid beta-Peptides - metabolism
Amyloid beta-Protein Precursor - genetics
Amyloidosis - genetics
Amyloidosis - therapy
Animals
Brain - drug effects
Brain - metabolism
Brain - pathology
Brief Communication
Cell Line
Disease Models, Animal
Drug Administration Routes
Frontal Lobe - drug effects
Frontal Lobe - metabolism
Frontal Lobe - pathology
Gene Transfer Techniques
Genes, Reporter
Genetic Therapy - methods
Genetic Vectors - administration & dosage
Genetic Vectors - genetics
Hippocampus - drug effects
Hippocampus - metabolism
Hippocampus - pathology
Humans
Kidney - cytology
Kidney - metabolism
Lentivirus - genetics
Mice
Mice, Transgenic
Neprilysin - biosynthesis
Neprilysin - genetics
Neprilysin - pharmacology
Peptide Fragments - metabolism
Plaque, Amyloid - drug effects
Plaque, Amyloid - pathology
Stem Cells - metabolism
Treatment Outcome
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Summary: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.
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.23-06-01992.2003