Beta amyloid-induced upregulation of death receptor 6 accelerates the toxic effect of N-terminal fragment of amyloid precursor protein

Amyloid precursor protein (APP) plays essential roles in the development of the Alzheimer's disease. Although full-length APP has been thoroughly studied, the role of the cleavage fragments especially the N-terminal fragments (N-APPs) in Alzheimer's disease pathogenesis was still elusive. In this study, we demonstrated that application of recombinant APP(18-286) could enhance beta amyloid (A beta)-induced neuronal injuries which were related to the activation of apoptosis proteins. A beta-treatment could induce a slight increase of N-APPs release. In addition, expression of death receptor 6 (DR6) was increased in A beta-treated neurons and APP transgenic mice. Moreover, the effect of APP(18-286) on A beta-induced injuries could be suppressed by the application of recombinant DR6(41-341) and DR6 antibody. Furthermore, pull-down assay revealed that APP(18-286) could bind both exogenous and endogenous DR6. A beta promoted APP(18-286) targeting to neuron which was accompanied with the increase of DR6 expression, whereas down-regulation of DR6 by interference RNA could alleviate the binding of N-APPs to neuron and also suppressed A beta-dependent toxic effect with N-APPs. These results suggested that APP N-terminal fragments might play neurotoxic roles in A beta-induced neuronal injuries through cell surface DR6. (C) 2015 Elsevier Inc. All rights reserved.