Antibody binding to cell surface amyloid precursor protein induces neuronal injury by deregulating the phosphorylation of focal adhesion signaling related proteins.
The biological function of full-length amyloid-beta protein precursor (APP), the precursor of Abeta, is not fully understood. Mounting studies reported that antibody binding to cell surface APP causes neuronal injury. However, the mechanism of cell surface APP mediating neuronal injury remains to be determined. Colocalization of APP with integrin on cell surface leads us to suppose that focal adhesion (FA) related mechanism is involved in surface APP-mediated neuronal injury. In the present study, results demonstrated that primary cultured neurons treated with antibody against APP-N-terminal not only caused neuronal injury and aberrant morphologic changes of neurite, but also induced reaction of FA proteins appearing an acute increase then decrease pattern. Moreover, the elevation of tyrosine phosphorylation of FA proteins including paxillin and focal adhesion kinase (FAK), and down-regulated expression of protein tyrosine phosphatase (PTP1B) induced by APP antibody were prevented by inhibitor of Src protein kinases 4-amino-5-(4-chlorophenyl)-7(t-butyl) pyrazol (3,4-D) pyramide (PP2) and G protein inhibitor pertussis toxin (PTX), implying that Src family kinase and G protein play roles in APP-induced FA signals. In addition, pretreatment with PTX and PP2 was able to suppress APP-antibody induced neuronal injury. Taken together, the results suggest a novel mechanism for APP mediating neuronal injury through deregulating FA signals.
Xu
Yu-Xia
YX
State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, PR China.
Wang
Hong-Quan
HQ
Yan
Jie
J
Sun
Xiao-Bo
XB
Guo
Jing-Chun
JC
Zhu
Cui-Qing
CQ
D016564:Amyloid beta-Protein Precursor / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000276:immunology*; D009474:Neurons / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*
D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D051416:Focal Adhesion Protein-Tyrosine Kinases