Expression of neprilysin in skeletal muscle reduces amyloid burden in a transgenic mouse model of alzheimer disease

Yinxing Liu, Christa Studzinski, Tina Beckett, Hanjun Guan, Matthew A. Hersh, M. Paul Murphy, Ronald Klein, Louis B. Hersh

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


Neprilysin (NEP) is a zinc metallopeptidase that efficiently degrades the amyloid β(A β) peptides believed to be involved in the etiology of Alzheimer disease (AD). The focus of this study was to develop a new and tractable therapeutic approach for treating AD using NEP gene therapy. We have introduced adeno-associated virus (AAV) expressing the mouse NEP gene into the hindlimb muscle of 6-month-old human amyloid precursor protein (hAPP) (3X-Tg-AD) mice, an age which correlates with early stage AD. Overexpression of NEP in muscle decreased brain soluble A β peptide levels by ˜60% and decreased amyloid deposits by ˜50%, with no apparent adverse effects. Expression of NEP on muscle did not affect the levels of a number of other physiological peptides known to be in vitro substrates. These findings demonstrate that peripheral expression of NEP and likely other peptidases represents an alternative to direct administration into brain and illustrates the potential for using NEP expression in muscle for the prevention and treatment of AD.

Original languageEnglish
Pages (from-to)1381-1386
Number of pages6
JournalMolecular Therapy
Issue number8
StatePublished - Aug 2009

Bibliographical note

Funding Information:
This study was supported by NIH grants DA 02243 from the National Institute on Drug Abuse, AG 24899 from the National Institute on Aging, and P20RR02017 from the National Center for Research Resources (NCRR). We thank Hansruedi Beuler for suggesting the use of muscle as a site for NEP expression. The University of Kentucky has filed a patent application based in part on these studies.

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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