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First published online 22 September 2009
doi: 10.1242/jcs.048090

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Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway

¹ Psychiatry Research, University of Zurich, August-Forel Strasse 1, 8008 Zurich, Switzerland
² Systems and Cell Biology of Neurodegeneration, University of Zurich, August-Forel Strasse 1, 8008 Zurich, Switzerland
³ Max-Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany

^* Author for correspondence (uwekon{at}bli.uzh.ch)

Accepted 22 July 2009

Proteolytic processing of the amyloid precursor protein (APP) occurs via two alternative pathways, localized to different subcellular compartments, which result in functionally distinct outcomes. Cleavage by a β- sequence generates the Aβ peptide that plays a central role in Alzheimer's disease. In the case of - cleavage, a secreted neurotrophic molecule is generated and the Aβ peptide cleaved and destroyed. In both cases, a cytosolic APP intracellular domain (AICD) is generated. We have previously shown that coexpression of APP with the APP-binding protein Fe65 and the histone acetyltransferase Tip60 results in the formation of nuclear complexes (termed AFT complexes), which localize to transcription sites. We now show that blocking endocytosis or the pharmacological or genetic inhibition of the endosomal β-cleavage pathway reduces translocation of AICD to these nuclear AFT complexes. AICD signaling further depends on active transport along microtubules and can be modulated by interference with both anterograde and retrograde transport systems. Nuclear signaling by endogenous AICD in primary neurons could similarly be blocked by inhibiting β-cleavage but not by -cleavage inhibition. This suggests that amyloidogenic cleavage, despite representing the minor cleavage pathway of APP, is predominantly responsible for AICD-mediated nuclear signaling.

Key words: AICD, Amyloid precursor protein, Endocytosis, Nuclear signaling, Retrograde transport

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