title: A DR6/p75(NTR) complex is responsible for β-amyloid-induced cortical neuron death.
abstract: The p75 neurotrophin receptor (p75(NTR)) is a known mediator of β-amyloid (Aβ)-induced neurotoxicity implicated in Alzheimer's disease (AD). Here, we demonstrate that death receptor 6 (DR6) binds to p75(NTR) and is a component of the p75(NTR) signaling complex responsible for Aβ-induced cortical neuron death. Cortical neurons isolated from either DR6 or p75(NTR) null mice are resistant to Aβ-induced neurotoxicity. Blocking DR6 function in cortical neurons by anti-DR6 antibodies that block the binding of DR6 to p75(NTR) receptor complex or by a dominant negative DR6 construct lacking the cytoplasmic signaling death domain attenuates Aβ-induced caspase 3 activation and cell death. DR6 expression is upregulated in AD cortex and correlates with elevated neuronal death. Targeting the disruption of the DR6/p75(NTR) complex to prevent Aβ cytotoxicity represents a new approach for the treatment of neurodegenerative disorders such as AD.
authors.affiliation: Department of Discovery Neurobiology, BiogenIdec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.forename: X
authors.initials: X
authors.lastname: Lee
authors.forename: Z
authors.initials: Z
authors.lastname: Shao
authors.forename: D
authors.initials: D
authors.lastname: Apicco
authors.forename: G
authors.initials: G
authors.lastname: Huang
authors.forename: B J
authors.initials: BJ
authors.lastname: Gong
authors.forename: R B
authors.initials: RB
authors.lastname: Pepinsky
authors.forename: S
authors.initials: S
authors.lastname: Mi
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D011485:Protein Binding; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C517634:Ngfr protein, mouse; C485251:Tnfrsf21 protein, mouse; D053148:Caspase 3
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