title: Physiological mouse brain Abeta levels are not related to the phosphorylation state of threonine-668 of Alzheimer's APP.
abstract: BACKGROUND
  Amyloid-beta peptide species ending at positions 40 and 42 (Abeta40, Abeta42) are generated by the proteolytic processing of the Alzheimer's amyloid precursor protein (APP). Abeta peptides accumulate in the brain early in the course of Alzheimer's disease (AD), especially Abeta42. The cytoplasmic domain of APP regulates intracellular trafficking and metabolism of APP and its carboxyl-terminal fragments (CTFalpha, CTFbeta). The role of protein phosphorylation in general, and that of the phosphorylation state of APP at threonine-668 (Thr668) in particular, has been investigated in detail by several laboratories (including our own). Some investigators have recently proposed that the phosphorylation state of Thr668 plays a pivotal role in governing brain Abeta levels, prompting the current study.
  
  
  METHODS
  In order to evaluate whether the phosphorylation state of Thr668 controlled brain Abeta levels, we studied the levels and subcellular distributions of holoAPP, sAPPalpha, sAPPbeta, CTFalpha, CTFbeta, Abeta40 and Abeta42 in brains from "knock-in" mice in which a non-phosphorylatable alanyl residue had been substituted at position 668, replacing the threonyl residue present in the wild-type protein.
  
  
  CONCLUSIONS
  The levels and subcellular distributions of holoAPP, sAPPalpha, sAPPbeta, CTFalpha, CTFbeta, Abeta40 and Abeta42 in the brains of Thr668Ala mutant mice were identical to those observed in wild-type mice. These results indicate that, despite speculation to the contrary, the phosphorylation state of APP at Thr668 does not play an obvious role in governing the physiological levels of brain Abeta40 or Abeta42 in vivo.
authors.affiliation: RIKEN, Brain Science Institute, Behavioral Genetics, Wako, Japan.
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Sano
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakaya
authors.forename: Steve
authors.initials: S
authors.lastname: Pedrini
authors.forename: Shizu
authors.initials: S
authors.lastname: Takeda
authors.forename: Kanae
authors.initials: K
authors.lastname: Iijima-Ando
authors.forename: Koichi
authors.initials: K
authors.lastname: Iijima
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
authors.forename: Sam
authors.initials: S
authors.lastname: Gandy
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000033:anatomy & histology / Q000254:growth & development / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013912:Threonine / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D010446:Peptide Fragments; D011994:Recombinant Proteins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D013912:Threonine