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Published online 17 October 2005. doi:10.1083/jcb.200505078
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 2, 327-335
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Article

Activation of GSK-3 and phosphorylation of CRMP2 in transgenic mice expressing APP intracellular domain



Kathleen A. Ryan and Sanjay W. Pimplikar

Department of Pathology and Cell Biology Program, Case Western Reserve University, Cleveland, OH 44106

Correspondence to Sanjay W. Pimplikar: sanjay.pimplikar{at}case.edu

Amyloid precursor protein (APP), implicated in Alzheimer's disease, is a trans-membrane protein of undetermined function. APP is cleaved by {gamma}-secretase that releases the APP intracellular domain (AICD) in the cytoplasm. In vitro studies have implicated AICD in cell signaling and transcriptional regulation, but its biologic relevance has been uncertain and its in vivo function has not been examined. To investigate its functional role, we generated AICD transgenic mice, and found that AICD causes significant biologic changes in vivo. AICD transgenic mice show activation of glycogen synthase kinase-3ß (GSK-3ß) and phosphorylation of CRMP2 protein, a GSK-3ß substrate that plays a crucial role in Semaphorin3a-mediated axonal guidance. Our data suggest that AICD is biologically relevant, causes significant alterations in cell signaling, and may play a role in axonal elongation or pathfinding.

Abbreviations used in this paper: AD, Alzheimer's disease; AICD, APP intracellular domain; APP, amyloid precursor protein; CRMP2, collapsin responsive mediator protein–2; CTF, COOH-terminal fragment; ERK, extracellular signal-regulated kinase; FAD, familial Alzheimer's disease; GSK, glycogen synthase kinase; Sema3a, Semaphorin3a.


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