A DR6/p75(NTR) complex is responsible for β-amyloid-induced cortical neuron death

• Published in: Cell death & disease 2013-04, Vol.4, p.e579
• Main Authors: Hu, Y, Lee, X, Shao, Z, Apicco, D, Huang, G, Gong, B J, Pepinsky, R B, Mi, S
• Format: Article
• Language: English
• Subjects: Amyloid beta-Peptides - pharmacology; Animals; Antibodies - pharmacology; Caspase 3 - genetics; Caspase 3 - metabolism; Cell Death - drug effects; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Gene Expression Regulation - drug effects; Mice; Mice, Knockout; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Primary Cell Culture; Protein Binding; Receptors, Nerve Growth Factor - deficiency; Receptors, Nerve Growth Factor - genetics; Receptors, Tumor Necrosis Factor - deficiency; Receptors, Tumor Necrosis Factor - genetics; Signal Transduction - drug effects
• ISSN: 2041-4889
• DOI: 10.1038/cddis.2013.110

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.