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J. Biol. Chem., Vol. 279, Issue 29, 30259-30264, July 16, 2004

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Effects of Neprilysin Chimeric Proteins Targeted to Subcellular Compartments on Amyloid Peptide Clearance in Primary Neurons^*

Emi Hama, Keiro Shirotani, Nobuhisa Iwata, and Takaomi C. Saido

From the Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

Neprilysin (NEP) is a rate-limiting amyloid peptide (A)-degrading enzyme in the brain. We demonstrated previously that overexpression of neprilysin in primary cortical neurons remarkably decreased not only extracellular but also intracellular A levels. To investigate the subcellular compartments where neprilysin degrades A most efficiently, we expressed neprilysin chimeric proteins containing various subcellular compartment-targeting domains in neurons. Sec12-NEP, -galactoside 2,6-sialyltransferase-NEP, transferrin receptor-NEP, and growth-associated protein 43-NEP were successfully sorted to the endoplasmic reticulum, trans-Golgi network, early/recycling endosomes, and lipid rafts, respectively. We found that intracellularly, wild-type neprilysin and all the chimeras showed equivalent A40-degrading activities. A40 was more effectively cleared than A42, and this tendency was greater for intracellular A than for extracellular A. Wild-type and trans-Golgi network-targeted ST-NEP cleared more intracellular A42 than the other chimeras. Wild-type neprilysin cleared extracellular A more effectively than any of the chimeras, among which endoplasmic reticulum-targeted Sec12-NEP was the least effective. These observations indicate that different intracellular compartments may be involved in the metabolism of distinct pools of A (A40 and A42) to be retained or recycled intracellularly and to be secreted extracellularly, and that the endogenous targeting signal in wild-type neprilysin is well optimized for the overall neuronal clearance of A.

Received for publication, February 20, 2004 , and in revised form, March 26, 2004.

^* This work was supported by research grants from RIKEN Brain Science Institute and the Ministry of Education, Culture, Sports, Science and Technology of Japan. 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.

To whom correspondence should be addressed. Tel.: 81-48-467-9715; Fax: 81-48-467-9716; E-mail: saido{at}brain.riken.go.jp.

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