Circulating neprilysin clears brain amyloid

Yinxing Liu, Christa Studzinski, Tina Beckett, M. Paul Murphy, Ronald L. Klein, Louis B. Hersh

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

The use of the peptidase neprilysin (NEP) as a therapeutic for lowering brain amyloid burden is receiving increasing attention. We have previously demonstrated that peripheral expression of NEP on the surface of hindlimb muscle lowers brain amyloid burden in a transgenic mouse model of Alzheimer's disease. In this study we now show that using adeno-associated virus expressing a soluble secreted form of NEP (secNEP-AAV8), NEP secreted into plasma is effective in clearing brain Aβ. Soluble NEP expression in plasma was sustained over the 3-month time period it was measured. Secreted NEP decreased plasma Aβ by 30%, soluble brain Aβ by ~. 28%, insoluble brain Aβ by ~. 55%, and Aβ oligomers by 12%. This secNEP did not change plasma levels of substance P or bradykinin, nor did it alter blood pressure. No NEP was detected in CSF, nor did the AAV virus produce brain expression of NEP. Thus the lowering of brain Aβ was due to plasma NEP which altered blood-brain Aβ transport dynamics. Expressing NEP in plasma provides a convenient way to monitor enzyme activity during the course of its therapeutic testing.

Original languageEnglish
Pages (from-to)101-107
Number of pages7
JournalMolecular and Cellular Neuroscience
Volume45
Issue number2
DOIs
StatePublished - Oct 2010

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 , P20RR02017 from the National Center for Research Resources (NCRR) , and a grant from the Kentucky Science and Engineering Foundation , KSTC-144-401-08-027 .

Keywords

  • Adeno-associated virus
  • Alzheimer's disease
  • Amyloid beta peptide
  • Gene therapy
  • Neprilysin

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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