Regulation of amyloid precursor protein (APP) phosphorylation and processing by p35/Cdk5 and p25/Cdk5

FEBS Letters

Zhou, Yan¹  Ryder, John¹  Su, Yuan¹  Li, Baolin¹  May, Patrick C¹  Liu, Feng¹  Gonzalez-DeWhitt, Patricia¹  Ni, Binhui¹ 

[1] Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA

关键词: Cyclin-dependent kinase 5;    p35;    p25;    Amyloid precursor protein;    Immature amyloid precursor protein;    Mature amyloid precursor protein;    Soluble amyloid precursor protein;    AD;    Alzheimer's disease;    APP;    amyloid precursor protein;    Aβ;    β-amyloid peptide;    Cdk5;    cyclin-dependent kinase 5;    imAPP;    immature APP;    mAPP;    mature APP;    sAPP;    soluble APP;    swAPP751;    APP751 bearing the Swedish mutation;   

DOI  :  10.1016/S0014-5793(03)00714-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The phosphorylation status of amyloid precursor protein (APP) at Thr668 is suggested to play a critical role in the proteolytic cleavage of APP, which generates either soluble APP_β (sAPP_β) and β-amyloid peptide (Aβ), the major component of senile plaques in patient brains inflicted with Alzheimer's disease (AD), or soluble APP_α (sAPP_α) and a peptide smaller than Aβ. One of the protein kinases known to phosphorylate APP^Thr668 is cyclin-dependent kinase 5 (Cdk5). Cdk5 is activated by the association with its regulatory partner p35 or its truncated form, p25, which is elevated in AD brains. The comparative effects of p35 and p25 on APP^Thr668 phosphorylation and APP processing, however, have not been reported. In this study, we investigated APP^Thr668 phosphorylation and APP processing mediated by p35/Cdk5 and p25/Cdk5 in the human neuroblastoma cell line SH-SY5Y. Transient overexpression of p35 and p25 elicited distinct patterns of APP^Thr668 phosphorylation, specifically, p35 increasing the phosphorylation of both mature and immature APP, whereas p25 primarily elevated the phosphorylation of immature APP. Despite these differential effects on APP phosphorylation, both p35 and p25 overexpression enhanced the secretion of Aβ, sAPP_β, as well as sAPP_α. These results confirm the involvement of Cdk5 in APP processing, and suggest that p35- and p25-mediated Cdk5 activities lead to discrete APP phosphorylation.

【 授权许可】

Unknown