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C-terminal fragments of amyloid precursor proteins increase cofilin phosphorylation by LIM kinase in cultured rat primary neurons

Cheng, Lin; Chen, Hui; Li, Cong; Xu, Cui; Xu, Yan-Ji

doi: 10.1097/WNR.0000000000001162
DEGENERATION AND REPAIR

Amyloid precursor proteins (APPs) are processed by β-, γ-, and ε-secretases and caspase-3 to generate C-terminal fragments of APP (APP-CTFs), which may contribute to the pathology of Alzheimer’s disease (AD). In addition to amyloid plaques and neurofibrillary tangles, AD brains contain Hirano bodies, which are rod-like structures mostly composed of actin and the actin-binding protein, cofilin. However, the mechanisms underlying the formation of cofilin-actin rods are still unknown. In this study, we aim to elucidate the effects of APP-CTFs on the actin-depolymerizing factor [(ADF)/cofilin]. Our data indicate that transfection with APP-CT99 and APP-CT57 may increase the phosphorylation level of Ser3 of ADF/cofilin and Thr508 of LIM-kinase 1 in rat primary cortical neuronal cultures. S3 peptide, a synthetic peptide competitor of LIM-kinase 1 for ADF/cofilin phosphorylation and an inhibitor of APP-CTFs, induced ADF/cofilin phosphorylation. In comparison with the wild-type mouse, the APP-CT transgenic mouse showed increased immunoreactivity of phosphorylated cofilin (p-cofilin) in the brain. Treatment with DAPT, an inhibitor of γ-secretase, resulted in a decrease in p-cofilin protein level in the group transfected with full-length APP-695. Transfection with the mutant APP-CTF with a deleted YENPTY domain resulted in no significant increase in p-cofilin level. Thus, APP-CTFs induced cofilin phosphorylation to facilitate nuclear translocation. These results suggest a relationship between APP-CTFs and ADF/cofilin that may be suggestive of a new toxic pathway in the pathology of AD.

Department of Preventive Medicine, Medical College of Yanbian University, Yanji, Jilin China

Correspondence to Yan-Ji Xu, PhD, Department of Preventive Medicine, Medical College of Yanbian University, Yanji, Jilin 133002, China Tel: +86 433 243 5173; e-mail: xuyanji@ybu.edu.cn

Received August 28, 2018

Accepted October 11, 2018

© 2019 Wolters Kluwer Health | Lippincott Williams & Wilkins