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 APP18-286 could enhance beta amyloid (Aβ)-induced neuronal injuries which were related to the activation of apoptosis proteins. Aβ treatment could induce a slight increase of N-APPs release. In addition, expression of death receptor 6 (DR6) was increased in Aβ-treated neurons and APP transgenic mice. Moreover, the effect of APP18-286 on Aβ-induced injuries could be suppressed by the application of recombinant DR641-341 and DR6 antibody. Furthermore, pull-down assay revealed that APP18-286 could bind both exogenous and endogenous DR6. Aβ promoted APP18-286 targeting to neuron which was accompanied with the increase of DR6 expression, whereas downregulation of DR6 by interference RNA could alleviate the binding of N-APPs to neuron and also suppressed Aβ-dependent toxic effect with N-APPs. These results suggested that APP N-terminal fragments might play neurotoxic roles in Aβ-induced neuronal injuries through cell surface DR6.