Direct visualization of the gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein: association with Fe65 and translocation to the nucleus
Article first published online: 7 AUG 2002
Journal of Neurochemistry
Volume 82, Issue 4, pages 839–847, August 2002
How to Cite
Kinoshita, A., Whelan, C. M., Smith, C. J., Berezovska, O. and Hyman, B. T. (2002), Direct visualization of the gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein: association with Fe65 and translocation to the nucleus. Journal of Neurochemistry, 82: 839–847. doi: 10.1046/j.1471-4159.2002.01016.x
- Issue published online: 7 AUG 2002
- Article first published online: 7 AUG 2002
- Received April 1, 2002; revised manuscript received April 29, 2002; accepted April 30, 2002.
- adapter protein;
- amyloid precursor protein;
- FRET, gamma cleavage;
- intracellular domain
Amyloid-β, the peptide that deposits as senile plaques in Alzheimer's disease, is derived from the amyloid precursor protein (APP) by a gamma secretase-mediated intramembranous cleavage. In addition to amyloid-β, this cleavage produces a carboxyl-terminal intracellular fragment which has an unknown function. The carboxyl-terminal domain of APP interacts in the cytoplasm with an adapter protein, Fe65. We demonstrate by laser scanning confocal microscopy that a gamma secretase generated APP carboxyl-terminal domain, tagged with green fluorescent protein (GFP), translocates to the nucleus in a manner dependent upon stabilization by the adapter protein Fe65; APP which has been mutated to block interactions with Fe65 cannot be detected in the nucleus. The APP-CT domain continues to interact with Fe65 in the nucleus, as determined by both colocalization and fluorescence resonance energy transfer (FRET). Visualization of the APP-CT-Fe65 complex in the nucleus may serve as a readout for processes that modify gamma secretase release of APP-CT.