Neprilysin Gene Transfer Reduces Human Amyloid Pathology in Transgenic Mice

• Published in: The Journal of neuroscience Vol. 23; no. 6; pp. 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: Journal Article
• Language: English
• Published: United States Soc Neuroscience 15-03-2003; Society for Neuroscience
• 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
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.23-06-01992.2003

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.