Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.

The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner.

Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.

The beta-amyloid precursor protein (APP) is a ubiquitous receptor-like molecule without a known function. However, the recent recognition that APP and Notch undergo highly similar proteolytic processing has suggested a potential signaling function for APP. After ligand binding, Notch is cleaved by the ADAM-17 metalloprotease followed by an intramembrane cleavage mediated by gamma-secretase. The gamma-secretase cut releases the Notch intracellular domain (NICD), which enters the nucleus and modulates transcription. Because APP is processed similarly by ADAM-17 and gamma-secretase, we reasoned that the APP intracellular domain (AICD) has a role analogous to the NICD. We therefore generated a plasmid encoding the AICD sequence and studied the subcellular localization of the expressed protein (C60). Our results demonstrate that the cytoplasmic domain of APP is a highly labile fragment that is stabilized by forming complexes with Fe65 and can then enter the nucleus in neurons and non-neural cells. These findings strongly support the hypothesis that APP signals in the nucleus in a manner analogous to the function of Notch.

J. Biol. Chem. 276:40288-40292(2001) [PubMed] [Europe PMC]