title: Beta amyloid-induced upregulation of death receptor 6 accelerates the toxic effect of N-terminal fragment of amyloid precursor protein.
abstract: 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.
authors.affiliation: State Key Laboratory of Medical Neurobiology, Department of Neurobiology and Institutes of Brain Science, School of Basic Medical Science, Fudan University, Shanghai, China.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Medical Neurobiology, Department of Neurobiology and Institutes of Brain Science, School of Basic Medical Science, Fudan University, Shanghai, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Chemistry and Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Neurobiology, Department of Neurobiology and Institutes of Brain Science, School of Basic Medical Science, Fudan University, Shanghai, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Shan
authors.affiliation: Department of Chemistry and Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Xiangshi
authors.initials: X
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Medical Neurobiology, Department of Neurobiology and Institutes of Brain Science, School of Basic Medical Science, Fudan University, Shanghai, China. Electronic address: cqzhu@shmu.edu.cn.
authors.forename: Cuiqing
authors.initials: C
authors.lastname: Zhu
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000502:physiology* / Q000633:toxicity*; D000818:Animals; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism* / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018124:Receptors, Tumor Necrosis Factor; C485251:Tnfrsf21 protein, mouse
keywords: Apoptosis pathway; Death receptor 6; N-terminal fragment of APP; β-Amyloid