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First published online August 26, 2004
doi: 10.1242/10.1242/jcs.01323
Research Article |
1 Division of Psychiatry Research, University of Zurich, August Forel-Str. 1, 8008 Zurich, Switzerland
2 Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Kita 12, Nishi-6, Sapporo, 060-0812, Japan
* Author for correspondence (e-mail: uwe.konietzko{at}bli.unizh.ch)
Accepted 24 May 2004
The physiological functions of the beta-amyloid precursor protein (APP) may include nuclear signaling. To characterize the role of the APP adaptor proteins Fe65, Jip1b, X11
(MINT1) and the chromatin-associated protein Tip60, we analyzed their interactions by confocal microscopy and co-immunoprecipitations. AICD corresponding to S3-cleaved APP bound to Fe65 that transported it to nuclei and docked it to Tip60. These proteins formed AICD-Fe65-Tip60 (AFT) complexes that were concentrated in spherical nuclear spots. 
-Secretase inhibitors prevented AFT-complex formation with AICD derived from full-length APP. The APP adaptor protein Jip1b also transported AICD to nuclei and docked it to Tip60, but AICD-Jip1b-Tip60 (AJT) complexes had different, speckle-like morphology. By contrast, X11 trapped AICD in the cytosol. Induced AICD expression identified the APP-effector genes APP, BACE, Tip60, GSK3ß and KAI1, but not the Notch-effector gene Hes1 as transcriptional targets. These data establish a role for APP in nuclear signaling, and they suggest that therapeutic strategies designed to modulate the cleavage of APP affect AICD-dependent signaling.
Key words: AICD, Alzheimer's disease, Tip60, Fe65, -Secretase, Transcriptional regulation
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