Work

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

Year: 2004

Type: article

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.

Source: Journal of Neuroscience

DOI: 10.1523/jneurosci.4580-03.2004