Tumor Necrosis Factor Death Receptor Signaling Cascade Is Required for Amyloid-β Protein-Induced Neuron Death

Rena Li, Libang Yang, Kristina Lindholm, Yoshihiro Konishi, Xu Yue, Harald Hampel, Dai Zhang, Yong Shen

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146 Scopus citations


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-β protein (Aβ), 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 Kκ (NF-κB). Aβ-induced neuronal apoptosis was reduced with lower Apaf-1 expression, andlittle NF-κB activation was found in the neurons with mutated Apaf-1 or a deletion of TNFRI comparedwith the cells from wild-type (WT) mice. Our studies suggest a novel neuronal response of Aβ, which occurs through a TNF receptor signaling cascade and a caspase-dependent death pathway.

Original languageEnglish (US)
Pages (from-to)1760-1771
Number of pages12
JournalJournal of Neuroscience
Issue number7
StatePublished - Feb 18 2004



  • Alzheimer
  • Apoptosis
  • Death
  • Degeneration
  • Neuron
  • Receptor

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