title: Increased amyloidogenic processing of transgenic human APP in X11-like deficient mouse brain.
abstract: BACKGROUND
  X11-family proteins, including X11, X11-like (X11L) and X11-like 2 (X11L2), bind to the cytoplasmic domain of amyloid β-protein precursor (APP) and regulate APP metabolism. Both X11 and X11L are expressed specifically in brain, while X11L2 is expressed ubiquitously. X11L is predominantly expressed in excitatory neurons, in contrast to X11, which is strongly expressed in inhibitory neurons. In vivo gene-knockout studies targeting X11, X11L, or both, and studies of X11 or X11L transgenic mice have reported that X11-family proteins suppress the amyloidogenic processing of endogenous mouse APP and ectopic human APP with one exception: knockout of X11, X11L or X11L2 has been found to suppress amyloidogenic metabolism in transgenic mice overexpressing the human Swedish mutant APP (APPswe) and the mutant human PS1, which lacks exon 9 (PS1dE9). Therefore, the data on X11-family protein function in transgenic human APP metabolism in vivo are inconsistent.
  
  
  RESULTS
  To confirm the interaction of X11L with human APP ectopically expressed in mouse brain, we examined the amyloidogenic metabolism of human APP in two lines of human APP transgenic mice generated to also lack X11L. In agreement with previous reports from our lab and others, we found that the amyloidogenic metabolism of human APP increased in the absence of X11L.
  
  
  CONCLUSIONS
  X11L appears to aid in the suppression of amyloidogenic processing of human APP in brain in vivo, as has been demonstrated by previous studies using several human APP transgenic lines with various genetic backgrounds. X11L appears to regulate human APP in a manner similar to that seen in endogenous mouse APP metabolism.
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita12-Nishi6, Kita-ku, Sapporo 060-0812, Japan. tsuzuki@pharm.hokudai.ac.jp.
authors.forename: Maho
authors.initials: M
authors.lastname: Kondo
authors.forename: Maki
authors.initials: M
authors.lastname: Shiono
authors.forename: Genzo
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authors.lastname: Itoh
authors.forename: Norio
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authors.lastname: Takei
authors.forename: Takahide
authors.initials: T
authors.lastname: Matsushima
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maeda
authors.forename: Hidenori
authors.initials: H
authors.lastname: Taru
authors.forename: Saori
authors.initials: S
authors.lastname: Hata
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Saito
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki