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.