Pin1 promotes production of Alzheimer's amyloid β from β-cleaved amyloid precursor protein

Hirotada Akiyama, Ryong Woon Shin, Chiyoko Uchida, Tetsuyuki Kitamoto, Takafumi Uchida

研究成果: Article査読

53 被引用数 (Scopus)

抄録

Here we show that prolyl isomerase Pin1 is involved in the Aβ production central to the pathogenesis of Alzheimer's disease. Enzyme immunoassay of brains of the Pin1-deficient mice revealed that production of Aβ40 and Aβ42 was lower than that of the wild-type mice, indicating that Pin1 promotes Aβ production in the brain. GST-Pin1 pull-down and immunoprecipitation assay revealed that Pin1 binds phosphorylated Thr668-Pro of C99. In the Pin1-/- MEF transfected with C99, Pin1 co-transfection enhanced the levels of Aβ40 and Aβ42 compared to that without Pin1 co-transfection. In COS7 cells transfected with C99, Pin1 co-transfection enhanced the generation of Aβ40 and Aβ42, and reduced the expression level of C99, facilitating the C99 turnover. Thus, Pin1 interacts with C99 and promotes its γ-cleavage, generating Aβ40 and Aβ42. Further, GSK3 inhibitor lithium blocked Pin1 binding to C99 by decreasing Thr668 phosphorylation and attenuated Aβ generation, explaining the inhibitory effect of lithium on Aβ generation.

本文言語English
ページ(範囲)521-529
ページ数9
ジャーナルBiochemical and biophysical research communications
336
2
DOI
出版ステータスPublished - 2005 10 21

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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