title: Phosphorylation of amyloid precursor protein (APP) at Thr668 regulates the nuclear translocation of the APP intracellular domain and induces neurodegeneration.
abstract: Amyloid precursor protein (APP) has eight potential phosphorylation sites in its cytoplasmic domain. Recently, it has demonstrated that the constitutive phosphorylation of APP at T668 (APP695 isoform numbering) was observed specifically in the brain. Neuron-specific phosphorylation of APP at T668 is thought to be important for neuronal functions of APP, although its exact physiological significance remains to be clarified. In this study, we show that the phosphorylation of the APP intracellular domain (AICD) at T668 is essential for its binding to Fe65 and its nuclear translocation and affects the resultant neurotoxicity, possibly mediated through the induction of glycogen synthase kinase 3beta and tau phosphorylation by enhancing the formation of a ternary complex with Fe65 and CP2 transcription factor. Taken together, these results suggest that the phosphorylation of AICD at T668 contributes to the neuronal degeneration in Alzheimer's disease (AD) by regulating its translocation into the nucleus and then affects neurodegeneration; therefore, the specific inhibitor of T668 phosphorylation might be the target of AD therapy.
authors.affiliation: Department of Pharmacology, College of Medicine, and National Creative Research Initiative Center for Alzheimer's Dementia, Seoul National University, Seoul 110-799, South Korea.
authors.forename: Keun-A
authors.initials: KA
authors.lastname: Chang
authors.forename: Hye-Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Ha
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Ha
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Shin
authors.forename: Yun Ha
authors.initials: YH
authors.lastname: Jeong
authors.forename: Jean-Pyo
authors.initials: JP
authors.lastname: Lee
authors.forename: Cheol-Hyoung
authors.initials: CH
authors.lastname: Park
authors.forename: Seonghan
authors.initials: S
authors.lastname: Kim
authors.forename: Tae-Kyoung
authors.initials: TK
authors.lastname: Baik
authors.forename: Yoo-Hun
authors.initials: YH
authors.lastname: Suh
mesh_terms: D021581:Active Transport, Cell Nucleus; D000544:Alzheimer Disease / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000473:pathology; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D013912:Threonine / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016875:tau Proteins; D013912:Threonine; D020932:Nerve Growth Factor; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3