Regulated intramembrane proteolysis (RIP) of the amyloid precursor protein (APP) producesamyloid
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-protein (A
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), the probable causative agent of Alzheimer's disease (AD), and is therefore animportant target for therapeutic intervention. However, there is a burgeoning consensus that
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-secretase,one of the proteases that generates A
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, is also critical for the signal transduction of APP and a growinglist of other receptors. APP is a member of a gene family that includes two amyloid precursor-like proteins,APLP1 and APLP2. Although APP and the APLPs undergo similar proteolytic processing, there is littleinformation about the role of their
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-secretase-generated intracellular domains (ICDs). Here, we showthat APLP1 and 2 undergo presenilin-dependent RIP similar to APP, resulting in the release of a ~6 kDaICD for each protein. Each of the ICDs are degraded by an insulin degrading enzyme-like activity, butthey can be stabilized by members of the FE65 family and translocate to the nucleus. Given that modulationof APP processing is a therapeutic target and that the APLPs are processed in a manner similar to APP,any strategy aimed at altering APP proteolysis will have to take into account possible effects on signalingby APLP 1 and 2.