Published online before print April 10, 2008

This Article Full Text (Rapid PDF) All Versions of this Article: ajpath.2008.070620v1 172/5/1342    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by El-Amouri, S. S. Articles by Kindy, M. S. Search for Related Content PubMed PubMed Citation Articles by El-Amouri, S. S. Articles by Kindy, M. S.

Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070620

Accepted for publication February 5, 2008.

Article

Neprilysin: An Enzyme Candidate to Slow the Progression of Alzheimer's Disease

Salim S. El-Amouri^*, Hong Zhu, Jin Yu, Robert Marr, Inder M. Verma, and Mark S. Kindy^*@

From the Departments of Molecular and Cellular Biochemistry,* and Neurosciences, Medical University of South Carolina, Charleston, South Carolina; the Ralph H. Johnson Veteran's Administration Medical Center, Charleston, South Carolina; and the Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California

^@ To whom correspondence should be addressed. E-mail: kindyms{at}musc.edu.

	Abstract

It is well established that the extracellular deposition of amyloid (A) peptide plays a central role in the development of Alzheimer's disease (AD). Therefore, either preventing the accumulation of A peptide in the brain or accelerating its clearance may slow the rate of AD onset. Neprilysin (NEP) is the dominant A peptide-degrading enzyme in the brain; NEP becomes inactivated and down-regulated during both the early stages of AD and aging. In this study, we investigated the effect of human (h)NEP gene transfer to the brain in a mouse model of AD before the development of amyloid plaques, and assessed how this treatment modality affected the accumulation of A peptide and associated pathogenetic changes (eg, inflammation, oxidative stress, and memory impairment). Overexpression of hNEP for 4 months in young APP/PS1 double-transgenic mice resulted in reduction in A peptide levels, attenuation of amyloid load, oxidative stress, and inflammation, and improved spatial orientation. Moreover, the overall reduction in amyloidosis and associated pathogenetic changes in the brain resulted in decreased memory impairment by 50%. These data suggest that restoring NEP levels in the brain at the early stages of AD is an effective strategy to prevent or attenuate disease progression.