Long-term neprilysin gene transfer is associated with reduced levels of intracellular Abeta and behavioral improvement in APP transgenic mice.

Full Abstract

BACKGROUND: Proteolytic degradation has emerged as a key pathway involved in controlling levels of the Alzheimer's disease (AD)-associated amyloid-beta (Abeta) peptide in the brain. The endopeptidase, neprilysin, has been implicated as a major Abeta degrading enzyme in mice and humans. Previous short and intermediate term studies have shown the potential therapeutic application of neprilysin by delivering this enzyme into the brain of APP transgenic mice using gene transfer with viral vectors. However the effects of long-term neprilysin gene transfer on other aspects of Abeta associated pathology have not been explored yet in APP transgenic mice. RESULTS: We show that the sustained expression of neprilysin for up to 6 months lowered not only the amyloid plaque load but also reduced the levels of intracellular Abeta immunoreactivity. This was associated with improved behavioral performance in the water maze and ameliorated the dendritic and synaptic pathology in the APP transgenic mice. CONCLUSION: These data support the possibility that long-term neprilysin gene therapy improves behavioral and neurodegenerative pathology by reducing intracellular Abeta.

Author information

Author/s: Spencer, Brian (B); Marr, Robert A (RA); Rockenstein, Edward (E); Crews, Leslie (L); Adame, Anthony (A); Potkar, Rewati (R); Patrick, Christina (C); Gage, Fred H (FH); Verma, Inder M (IM); Masliah, Eliezer (E);

Affiliation: Department of Neurosciences, University of California San Diego, La Jolla, California 92093, USA. b1spencer(-atsign-)ucsd.edu

Grants: AG022074 (Agency:NIA NIH HHS) ; AG10435 (Agency:NIA NIH HHS) ; AG18440 (Agency:NIA NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: BMC neuroscience (BMC Neurosci), published in England. (Language: eng)

Reference: 2008-; vol 9 (issue ) : pp 109

Dates: Created 2008/12/05; Completed 2008/12/19;

PMID: 19014502, status: MEDLINE (last retrieved date: 2/18/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

External Links for this article
(including full text providers, if available):

Click Electronic Full-text Provider Links to see options for finding the electronic full text links to this article. Note there may be a subscription or fee required for access to the full text. See our FAQ for information on finding FREE full text articles.

This article may also be located in paper journal collections available in many libraries. Use the Journal and Publication Information above to find the full article.