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PMID:12657655

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Citation

Marr, RA, Rockenstein, E, Mukherjee, A, Kindy, MS, Hersh, LB, Gage, FH, Verma, IM and Masliah, E (2003) Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. J. Neurosci. 23:1992-6

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.

Links

PubMed

Keywords

Alzheimer Disease/genetics; Amyloid beta-Peptides/metabolism; Amyloid beta-Protein Precursor/genetics; Amyloidosis/genetics; Amyloidosis/therapy; Animals; Brain/drug effects; Brain/metabolism; Brain/pathology; 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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NEP

involved_in

GO:0097242: amyloid-beta clearance

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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