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

• Published in: Biochemical and biophysical research communications 2005-10, Vol.336 (2), p.521-529
• Main Authors: Akiyama, Hirotada, Shin, Ryong-Woon, Uchida, Chiyoko, Kitamoto, Tetsuyuki, Uchida, Takafumi
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Amyloid β; Animals; Brain - metabolism; Cells, Cultured; Fibroblasts - metabolism; GSK-3β; Lithium; Mice; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase - deficiency; Peptidylprolyl Isomerase - metabolism; Pin1; γ-Secretase cleavage
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2005.08.130

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.