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

Cell Death Dis. 2013 Apr 4;4(4):e579. doi: 10.1038/cddis.2013.110.

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.

MeSH terms

  • 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

Substances

  • Amyloid beta-Peptides
  • Antibodies
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • TNFRSF16 protein, mouse
  • Tnfrsf21 protein, mouse
  • Caspase 3