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The Journal of Neuroscience, January 28, 2009, 29(4):1115-1125; doi:10.1523/JNEUROSCI.4220-08.2009

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Neurobiology of Disease
Neuropeptide Y Fragments Derived from Neprilysin Processing Are Neuroprotective in a Transgenic Model of Alzheimer's Disease

John B. Rose,¹ Leslie Crews,² Edward Rockenstein,¹ Anthony Adame,¹ Michael Mante,¹ Louis B. Hersh,³ Fred H. Gage,⁴ Brian Spencer,¹ Rewati Potkar,¹ Robert A. Marr,⁵ and Eliezer Masliah^1,2

Departments of ¹Neurosciences and ²Pathology, University of California, San Diego, La Jolla, California 92093, ³Department of Biochemistry, University of Kentucky, Lexington, Kentucky 40563-0298, ⁴Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, and ⁵Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064

Correspondence should be addressed to Dr. Eliezer Masliah, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624. Email: emasliah{at}ucsd.edu

The endopeptidase neprilysin (NEP) is a major amyloid-β (Aβ) degrading enzyme and has been implicated in the pathogenesis of Alzheimer's disease. Because NEP cleaves substrates other than Aβ, we investigated the potential role of NEP-mediated processing of neuropeptides in the mechanisms of neuroprotection in vivo. Overexpression of NEP at low levels in transgenic (tg) mice affected primarily the levels of neuropeptide Y (NPY) compared with other neuropeptides. Ex vivo and in vivo studies in tg mice and in mice that received lentiviral vector injections showed that NEP cleaved NPY into C-terminal fragments (CTFs), whereas silencing NEP reduced NPY processing. Immunoblot and mass spectrometry analysis showed that NPY 21–36 and 31–36 were the most abundant fragments generated by NEP activity in vivo. Infusion of these NPY CTFs into the brains of APP (amyloid precursor protein) tg mice ameliorated the neurodegenerative pathology in this model. Moreover, the amidated NPY CTFs protected human neuronal cultures from the neurotoxic effects of Aβ. This study supports the possibility that the NPY CTFs generated during NEP-mediated proteolysis might exert neuroprotective effects in vivo. This function of NEP represents a unique example of a proteolytic enzyme with dual action, namely, degradation of Aβ as well as processing of NPY.

Key words: neuropeptide; neprilysin; Alzheimer's disease; cleavage; processing; amyloid

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Received Sept. 3, 2008; revised Nov. 5, 2008; accepted Dec. 8, 2008.

Correspondence should be addressed to Dr. Eliezer Masliah, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624. Email: emasliah{at}ucsd.edu

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