Published online before print April 10, 2008

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(American Journal of Pathology. 2008;172:1342-1354.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070620

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

It is well established that the extracellular deposition of amyloid β (Aβ) peptide plays a central role in the development of Alzheimer’s disease (AD). Therefore, either preventing the accumulation of Aβ peptide in the brain or accelerating its clearance may slow the rate of AD onset. Neprilysin (NEP) is the dominant Aβ 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 Aβ 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 Aβ 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.

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