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Journal of Molecular Neuroscience

, Volume 22, Issue 1–2, pp 5–11 | Cite as

Neprilysin regulates amyloid β peptide levels

  • Robert A. Marr
  • Hanjun Guan
  • Edward Rockenstein
  • Mark Kindy
  • Fred H. Gage
  • Inder Verma
  • Eliezer Masliah
  • Louis B. Hersh
Alzheimer’s Research

Abstract

That neprilysin (NEP) is a major Aβ peptide-degrading enzyme in vivo is shown by higher Aβ peptide levels in the brain of an NEP knockout mouse. In addition, we show that infusion of an NEP inhibitor, but not inhibitors of other peptidases, into the brains of an APP transgenic mouse elevates Aβ levels. We have investigated the use of NEP as a potential therapeutic agent to prevent the accumulation of Aβ peptides in the brain. Lentivirus expressing NEP was initially used to demonstrate the ability of the enzyme to reduce Aβ levels in a model CHO cell line and to make primary hippocampal neurons resistant to Aβ-mediated neurotoxicity. Injection of NEP-expressing lentivirus, but not inactive NEP-expressing lentivirus, GFP-expressing lentivirus, or vehicle, into the hippocampus of 12–20-mo-old hAPP transgenic mice led to an approx 50% reduction in the number of amyloid plaques. These studies provide the impetus for further investigating of the use of NEP in a gene transfer therapy paradigm to prevent the accumulation of Aβ and prevent or delay the onset of Alzheimer’s disease.

Keywords

Molecular Neuroscience Volume Primary Hippocampal Neuron 7PA2 Cell hAPP Transgenic Mouse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Robert A. Marr
    • 1
  • Hanjun Guan
    • 3
  • Edward Rockenstein
    • 2
  • Mark Kindy
    • 3
  • Fred H. Gage
    • 1
  • Inder Verma
    • 1
  • Eliezer Masliah
    • 2
  • Louis B. Hersh
    • 3
  1. 1.Laboratory of GeneticsSalk InstituteLa Jolla
  2. 2.Department of NeurosciencesThe University of California San DiegoLa Jolla
  3. 3.Department of Cellular and Molecular BiochemistryUniversity of KentuckyLexington

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