JNK-interacting protein-1 promotes transcription of Aβ protein precursor but not Aβ precursor-like proteins, mechanistically different than Fe65

Processing of the amyloid beta protein precursor (AbetaPP) by the beta and gamma secretases leads to the production of two small peptides, amyloid beta and the AbetaPP intracellular domain (AID, or called elsewhere AICD). Whereas the role of amyloid beta in the pathogenesis of Alzheimer's disease has been studied extensively, only recently has information begun to accumulate as to the role of AID. Functions identified for AID include its ability to trigger apoptosis and a role in regulating gene transcription, particularly in combination with the AbetaPP binding protein Fe65. Here, we report that AID in combination with Janus kinase interacting protein-1 (JIP-1) can activate gene expression. We demonstrate that the mechanism is different from activation in combination with Fe65 by first showing that although Fe65 enters the nucleus in the absence of full-length AbetaPP, JIP-1 does not. Additionally, JIP-1-induced activation is Tip60 independent, whereas a complex with AID, Fe65, and Tip60 is formed for Fe65-induced activation. Finally, and probably most interestingly, we show that although the AbetaPP family members APLP1 and APLP2 (for amyloid beta precursor-like protein) can cause activation in combination with Fe65, APLP1 and APLP2 show little or no activation in combination with JIP-1. This activity for the AID fragment may help explain the unique functions of APPP relative to its other family members, and changes in gene expression found in Alzheimer's disease.