title: Wnt/β-catenin signal pathway stabilizes APP intracellular domain (AICD) and promotes its transcriptional activity.
abstract: Amyloid precursor protein (APP), a key protein in pathogenesis of Alzheimer's disease (AD), is a type I transmembrane protein which can be cleaved by β- and γ-secretase to release the amyloidogenic β-amyloid peptides (Aβ) and the APP intracellular domain (AICD). While Aβ has been widely believed to initiate pathogenic cascades culminating AD, the physiological functions and regulations of AICD remain elusive. In present study, endogenous AICD was demonstrated to be increased by canonical Wnt signal. Instead of due to γ-secretase activity, enhanced AICD expression was found due to the increased protein stability by Wnt/β-catenin. β-Catenin was demonstrated to be an associating partner of AICD, capable of promoting AICD mediated transcriptional activity. Investigation by AICD mutants proved that Fe65, a previously identified AICD binding partner, is not involved in this regulation. Taken together, our results suggest that AICD is stabilized and the AICD mediated transcriptional activity is promoted by canonical Wnt/β-catenin signaling independent of Fe65.
authors.affiliation: State Key laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Leiden University Medical Center, Dept. of Molecular Cell Biology, Leiden, The Netherlands.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhou
authors.forename: Kai
authors.initials: K
authors.lastname: Gong
authors.forename: Theo
authors.initials: T
authors.lastname: van Laar
authors.forename: Yandao
authors.initials: Y
authors.lastname: Gong
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051153:Wnt Proteins; D051176:beta Catenin