Neprilysin gene transfer reduces human amyloid pathology in transgenic mice

Robert A. Marr, Edward Rockenstein, Atish Mukherjee, Mark S. Kindy, Louis B. Hersh, Fred H. Gage, Inder M. Verma, Eliezer Masliah

Research output: Contribution to journalArticlepeer-review

346 Scopus citations

Abstract

The degenerative process of Alzheimer's disease is linked to a shift in the balance between amyloid-β (Aβ) production, clearance, and degradation. Neprilysin has recently been implicated as a major extracellular Aβ degrading enzyme in the brain. However, there has been no direct demonstration that neprilysin antagonizes the deposition of amyloid-β 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-β 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.

Original languageEnglish
Pages (from-to)1992-1996
Number of pages5
JournalJournal of Neuroscience
Volume23
Issue number6
DOIs
StatePublished - Mar 15 2003

Keywords

  • Alzheimer's disease
  • Amyloid-β
  • Endopeptidase
  • Gene therapy
  • Lentivirus
  • Neprilysin

ASJC Scopus subject areas

  • General Neuroscience

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