Tumor necrosis factor death receptor signaling cascade is required for amyloid-beta protein-induced neuron death

J Neurosci. 2004 Feb 18;24(7):1760-71. doi: 10.1523/JNEUROSCI.4580-03.2004.

Abstract

Tumor necrosis factor type I receptor (TNFRI), a death receptor, mediates apoptosis and plays a crucial role in the interaction between the nervous and immune systems. A direct link between death receptor activation and signal cascade-mediated neuron death in brains with neurodegenerative disorders remains inconclusive. Here, we show that amyloid-beta protein (Abeta), a major component of plaques in the Alzheimer's diseased brain, induces neuronal apoptosis through TNFRI by using primary neurons overexpressing TNFRI by viral infection or neurons from TNFRI knock-out mice. This was mediated via alteration of apoptotic protease-activating factor (Apaf-1) expression that in turn induced activation of nuclear factor kappaB (NF-kappaB). Abeta-induced neuronal apoptosis was reduced with lower Apaf-1 expression, and little NF-kappaB activation was found in the neurons with mutated Apaf-1 or a deletion of TNFRI compared with the cells from wild-type (WT) mice. Our studies suggest a novel neuronal response of Abeta, which occurs through a TNF receptor signaling cascade and a caspase-dependent death pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / physiology
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Antigens, CD / genetics*
  • Antigens, CD / metabolism
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptotic Protease-Activating Factor 1
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cytoplasm / metabolism
  • Gene Targeting
  • Genes, Reporter
  • Hippocampus / cytology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism*
  • Peptide Fragments / toxicity*
  • Proteins / genetics
  • Proteins / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Tumor Necrosis Factor / genetics*
  • Receptors, Tumor Necrosis Factor / metabolism
  • Receptors, Tumor Necrosis Factor, Type I
  • Signal Transduction / physiology*
  • Transfection
  • Up-Regulation / drug effects

Substances

  • APAF1 protein, human
  • Amyloid beta-Peptides
  • Antigens, CD
  • Apaf1 protein, mouse
  • Apoptotic Protease-Activating Factor 1
  • NF-kappa B
  • Peptide Fragments
  • Proteins
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • amyloid beta-protein (1-40)