title: Fe65 stimulates proteolytic liberation of the beta-amyloid precursor protein intracellular domain.
abstract: The beta-amyloid precursor protein (APP)-binding protein Fe65 is involved in APP nuclear signaling and several steps in APP proteolytic processing. In this study, we show that Fe65 stimulates gamma-secretase-mediated liberation of the APP intracellular domain (AICD). The mechanism of Fe65-mediated stimulation of AICD formation appears to be through enhanced production of the carboxyl-terminal fragment substrates of gamma-secretase and direct stimulation of processing by gamma-secretase. The stimulatory capacity of Fe65 is isoform-dependent, as the non-neuronal and a2 isoforms promote APP processing more effectively than the exon 9 inclusive neuronal form of Fe65. Intriguingly, Fe65 stimulation of AICD production appears to be inversely related to pathogenic beta-amyloid production as the Fe65 isoforms profoundly stimulate AICD production and simultaneously decrease Abeta42 production. Despite the capacity of Fe65 to stimulate gamma-secretase-mediated APP proteolysis, it does not rescue the loss of proteolytic function associated with the presenilin-1 familial Alzheimer disease mutations. These data suggest that Fe65 regulation of APP proteolysis may be integrally associated with its nuclear signaling function, as all antecedent proteolytic steps prior to release of Fe65 from the membrane are fostered by the APP-Fe65 interaction.
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington 98195.
authors.forename: Jesse C
authors.initials: JC
authors.lastname: Wiley
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington 98195.
authors.forename: Elise A
authors.initials: EA
authors.lastname: Smith
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, Washington, 98195.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Hudson
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington 98195.
authors.forename: Warren C
authors.initials: WC
authors.lastname: Ladiges
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington 98195. Electronic address: mab@u.washington.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Bothwell
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D015398:Signal Transduction
chemical_list: C091042:APBB1 protein, human; D016229:Amyloid beta-Peptides; C486243:Apbb1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D053829:Amyloid Precursor Protein Secretases