Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription.

The familial Alzheimer's disease gene product beta-amyloid (Abeta) precursor protein (APP) is processed by the beta- and gamma-secretases to produce Abeta as well as AID (APP Intracellular Domain) which is derived from the extreme carboxyl terminus of APP. AID was originally shown to lower the cellular threshold to apoptosis and more recently has been shown to modulate gene expression such that it represses Notch-dependent gene expression while in combination with Fe65 it enhances gene activation. Here we report that the two other members of the APP family, beta-amyloid precursor-like protein-1 and -2 (APLP1 and APLP2), are also processed by the gamma-secretase in a Presenilin 1-dependent manner. Furthermore, the extreme carboxyl-terminal fragments produced by this processing (here termed APP-like Intracellular Domain or ALID1 and ALID2) are able to enhance Fe65-dependent gene activation, similar to what has been reported for AID. Considering that only APP and not the APLPs have been linked to familial Alzheimer's disease (AD), this data should help in understanding the physiologic roles of the APP family members and in differentiating these functions from the pathologic role of APP in Alzheimer's disease.