HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 27, 19066-19076, July 4, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/27/19066    most recent M710509200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Iijima-Ando, K. Articles by Iijima, K. Search for Related Content PubMed PubMed Citation Articles by Iijima-Ando, K. Articles by Iijima, K. Social Bookmarking                      What's this?

Overexpression of Neprilysin Reduces Alzheimer Amyloid-β42 (Aβ42)-induced Neuron Loss and Intraneuronal Aβ42 Deposits but Causes a Reduction in cAMP-responsive Element-binding Protein-mediated Transcription, Age-dependent Axon Pathology, and Premature Death in Drosophila^*

Kanae Iijima-Ando¹, Stephen A. Hearn^¶, Linda Granger^||, Christopher Shenton, Anthony Gatt^||, Hsueh-Cheng Chiang^¶**, Inessa Hakker^¶, Yi Zhong^¶, and Koichi Iijima^||2

From the Laboratory of Neurogenetics and Pathobiology, ^||Laboratory of Neurodegenerative Diseases and Gene Discovery, Farber Institute for Neurosciences, Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, ^¶Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, and the ^**Department of Neurobiology and Behavior, State University of New York, Stony Brook, New York 11794

The amyloid-β42 (Aβ42) peptide has been suggested to play a causative role in Alzheimer disease (AD). Neprilysin (NEP) is one of the rate-limiting Aβ-degrading enzymes, and its enhancement ameliorates extracellular amyloid pathology, synaptic dysfunction, and memory defects in mouse models of Aβ amyloidosis. In addition to the extracellular Aβ, intraneuronal Aβ42 may contribute to AD pathogenesis. However, the protective effects of neuronal NEP expression on intraneuronal Aβ42 accumulation and neurodegeneration remain elusive. In contrast, sustained NEP activation may be detrimental because NEP can degrade many physiological peptides, but its consequences in the brain are not fully understood. Using transgenic Drosophila expressing human NEP and Aβ42, we demonstrated that NEP efficiently suppressed the formation of intraneuronal Aβ42 deposits and Aβ42-induced neuron loss. However, neuronal NEP overexpression reduced cAMP-responsive element-binding protein-mediated transcription, caused age-dependent axon degeneration, and shortened the life span of the flies. Interestingly, the mRNA levels of endogenous fly NEP genes and phosphoramidon-sensitive NEP activity declined during aging in fly brains, as observed in mammals. Taken together, these data suggest both the protective and detrimental effects of chronically high NEP activity in the brain. Down-regulation of NEP activity in aging brains may be an evolutionarily conserved phenomenon, which could predispose humans to developing late-onset AD.

Received for publication, December 26, 2007 , and in revised form, April 1, 2008.

^* This work was supported, in whole or in part, by a National Institutes of Health grant (to Y. Z.). This work was also supported by an Alzheimer Association and Pilot Research award from Thomas Jefferson University (to K. I.), and start-up funds from Farber Institute for Neurosciences (to K. I. and K. I.-A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: 900 Walnut St., JHN410, Philadelphia, PA 19107. Fax: 215-955-4949; E-mail: Kanae.Iijima-Ando{at}jefferson.edu.

² To whom correspondence may be addressed. 900 Walnut St., JHN410, Philadelphia, PA 19107. Fax: 215-955-4949; E-mail: Koichi.Iijima{at}jefferson.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. B. Rose, L. Crews, E. Rockenstein, A. Adame, M. Mante, L. B. Hersh, F. H. Gage, B. Spencer, R. Potkar, R. A. Marr, et al. Neuropeptide Y Fragments Derived from Neprilysin Processing Are Neuroprotective in a Transgenic Model of Alzheimer's Disease J. Neurosci., January 28, 2009; 29(4): 1115 - 1125. [Abstract] [Full Text] [PDF]