Peripherally expressed neprilysin reduces brain amyloid burden: A novel approach for treating Alzheimer's disease

Hanjun Guan, Yinxing Liu, Abigail Daily, Sara Police, Myung Hee Kim, Salvatore Oddo, Frank M. LaFerla, James R. Pauly, M. Paul Murphy, Louis B. Hersh

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

A number of therapeutic strategies for treating Alzheimer's disease have focused on reducing amyloid burden in the brain. Among these approaches, the expression of amyloid β peptide (Aβ)-degrading enzymes in the brain has been shown to be effective but to date not practical for treating patients. We report here a novel strategy for lowering amyloid burden in the brain by peripherally expressing the Aβ-degrading enzyme neprilysin on leukocytes in the 3×Tg-AD mouse model of Alzheimer's disease. Through transplantation of lentivirus-transduced bone marrow cells, the Aβ-degrading protease neprilysin was expressed on the surface of leukocytes. This peripheral neprilysin reduced soluble brain Aβ peptide levels by ∼30% and lowered the accumulation of amyloid β peptides by 50-60% when transplantation was performed at both young and early adult age. In addition, peripheral neprilysin expression reduced amyloid-dependent performance deficits as measured by the Morris water maze. Unlike other methods designed to lower Aβ levels in blood, which cause a net increase in peptide, neprilysin expression results in the catabolism of Aβ to small, innocuous peptide fragments. These findings demonstrate that peripherally expressed neprilysin, and likely other Aβ-degrading enzymes, has the potential to be utilized as a therapeutic approach to prevent and treat Alzheimer's disease and suggest that this approach should be explored further.

Original languageEnglish (US)
Pages (from-to)1462-1473
Number of pages12
JournalJournal of Neuroscience Research
Volume87
Issue number6
DOIs
StatePublished - May 1 2009

Keywords

  • Amyloid clearance
  • Gene therapy
  • Peptidases

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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    Guan, H., Liu, Y., Daily, A., Police, S., Kim, M. H., Oddo, S., LaFerla, F. M., Pauly, J. R., Murphy, M. P., & Hersh, L. B. (2009). Peripherally expressed neprilysin reduces brain amyloid burden: A novel approach for treating Alzheimer's disease. Journal of Neuroscience Research, 87(6), 1462-1473. https://doi.org/10.1002/jnr.21944