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J. Biol. Chem., Vol. 282, Issue 14, 10203-10209, April 6, 2007

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IGF-1-induced Processing of the Amyloid Precursor Protein Family Is Mediated by Different Signaling Pathways^*

Linda Adlerz, Sofia Holback, Gerd Multhaup, and Kerstin Iverfeldt¹

From the Department of Neurochemistry, Stockholm University, SE-10691 Stockholm, Sweden and the Institute for Chemistry and Biochemistry, Free University of Berlin, D-14195 Berlin, Germany

The mammalian amyloid precursor protein (APP) protein family consists of the APP and the amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2). The neurotoxic amyloid -peptide (A) originates from APP, which is the only member of this protein family implicated in Alzheimer disease. However, the three homologous proteins have been proposed to be processed in similar ways and to have essential and overlapping functions. Therefore, it is also important to take into account the effects on the processing and function of the APP-like proteins in the development of therapeutic drugs aimed at decreasing the production of A. Insulin and insulin-like growth factor-1 (IGF-1) have been shown to regulate APP processing and the levels of A in the brain. In the present study, we show that IGF-1 increases -secretase processing of endogenous APP and also increases ectodomain shedding of APLP1 and APLP2 in human SH-SY5Y neuroblastoma cells. We also investigated the role of different IGF-1-induced signaling pathways, using specific inhibitors for phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK). Our results indicate that phosphatidylinositol 3-kinase is involved in ectodomain shedding of APP and APLP1, but not APLP2, and that MAPK is involved only in the ectodomain shedding of APLP1.

Received for publication, December 6, 2006 , and in revised form, February 2, 2007.

^* This work was supported by the Magn. Bergvalls Stiftelse, Alzheimerfonden, Längmanska kulturfonden and Stiftelsen för Gamla Tjänarinnor. 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. Tel.: 46-8-164268; Fax: 46-8-161371; E-mail: kerstin{at}neurochem.su.se.

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