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J. Biol. Chem., Vol. 281, Issue 17, 11933-11939, April 28, 2006

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The Cytosolic Loop of the -Secretase Component Presenilin Enhancer 2 Protects Zebrafish Embryos from Apoptosis^*

From the Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

The -secretase complex, composed of presenilin, presenilin enhancer 2 (Pen-2), nicastrin, and Aph-1, catalyzes the final cleavage of amyloid precursor protein to generate the toxic amyloid protein, the major component of plaques in the brains of Alzheimer disease patients. To understand the in vivo function of Pen-2, we used morphant technology available in zebrafish and transiently knocked down the expression of endogenous Pen-2 by injecting the morpholino (MO) against Pen-2. Two truncated Pen-2 proteins lacking either the cytosolic or the C-terminal domain were expressed in MO-injected embryos. This deletion analysis demonstrated that the Pen-2 cytosolic loop is essential for protecting developing embryos from caspase-dependent apoptosis caused by the reduction of Pen-2. Twelve amino acids in the C terminus of Pen-2 were dispensable and could not rescue the Pen-2 knockdown-induced apoptotic phenotype. Surprisingly, double knockdown of Pen-2 and nuclear factor B component p65 abrogated the single Pen-2 MO-induced caspase activation, indicating that a previously reported pro-apoptotic role of NF-B in some cell types could be manifested in a whole animal and that knockdown of Pen-2 may trigger pro-apoptotic activation of NF-B.

Received for publication, November 22, 2005 , and in revised form, February 16, 2006.

^* This work was supported by funds from the Göteborg Medical Society, the Swedish Society for Medical Research, the Wenner-Gren Foundation, the Fulbright Commission, and the Swedish Medical Society (to H. Z.); by funds from the Harvard Center for Neurodegeneration and Repair (to W. A. C. and W. X.); and by National Institutes of Health Grant AG015379 (to W. X.). 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 should be addressed: Center for Neurologic Diseases, Harvard Institutes of Medicine, HIM 616, 77 Ave. Louis Pasteur, Boston, MA 02115. Tel.: 617-525-5212; Fax: 617-525-5252; E-mail: wxia{at}rics.bwh.harvard.edu.

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