Abstract
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.
Highlights
The familial Alzheimer’s disease gene product -amyloid (A) precursor protein (APP) is processed by the and ␥-secretases to produce A as well as AID (APP Intracellular Domain) which is derived from the extreme carboxyl terminus of APP
In this report we show that APLP1 and APLP2 are substrates of the ␥-secretase and are processed to release ALID1 and ALID2
APLP1 and APLP2 Are Cleaved by the ␥-Secretase in a PS1dependent Manner—Since APP signals by releasing the biologically active AID peptide, we sought to investigate whether APLP1 and APLP2 release biologically active ALIDs due to processing by the ␥-secretase
Summary
Vol 277, No 46, Issue of November 15, pp. 44195–44201, 2002 Printed in U.S.A. Processing of -Amyloid Precursor-like Protein-1 and -2 by ␥-Secretase Regulates Transcription*. The familial Alzheimer’s disease gene product -amyloid (A) precursor protein (APP) is processed by the and ␥-secretases to produce A as well as AID (APP Intracellular Domain) which is derived from the extreme carboxyl terminus of APP. We report that the two other members of the APP family, -amyloid precursor-like protein-1 and -2 (APLP1 and APLP2), are processed by the ␥-secretase in a Presenilin 1-dependent manner. 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. Additional peptide termed AID, extending from the ␥-secretase cleavage site to the carboxyl terminus of APP, is produced following ␥-secretase cleavage regardless of whether it was preceded by ␣ or  cleavage This AID peptide was first identified in the brains of patients with AD and normal controls, and was shown to either induce or sensitize cells to apoptosis (7, 8). We show that full-length APLPs restrict Fe65 from entering the nucleus prior to ␥-secretase processing
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
