One mechanism leading to neurodegeneration during Alzheimer’s disease (AD) is amyloid β peptide (Aβ) neurotoxicity. Aβ elicits in cultured central nervous system neurons a biphasic response: a low-dose neurotrophic response and a high-dose neurotoxic response. Previously we reported that NF-κB is activated by low doses of Aβ only. Here we show that NF-κB activation leads to neuroprotection. In primary neurons we found that a pretreatment with 0.1 μM Aβ-(1–40) protects against neuronal death induced with 10 μM Aβ-(1–40). As a known neuroprotective agent we next analyzed the effect of tumor necrosis factor α (TNF-α). Maximal activation of NF-κB was found with 2 ng/ml TNF-α. Pretreatment with TNF-α protected cerebellar granule cells from cell death induced by 10 μM Aβ-(1–40). This protection is described by an inverted U-shaped dose response and is maximal with a NF-κB-activating dose. The molecular specificity of this protective effect was analyzed by specific blockade of NF-κB activation. Overexpression of a transdominant negative IκB-α blocks NF-κB activation and potentiates Aβ-mediated neuronal apoptosis. Our findings show that activation of NF-κB is the underlying mechanism of the neuroprotective effect of low-dose Aβ and TNF-α. In accordance with these in vitro data we find that nuclear NF-κB immunoreactivity around various plaque stages of AD patients is reduced in comparison to age-matched controls. Taken together these data suggest that pharmacological NF-κB activation may be a useful approach in the treatment of AD and related neurodegenerative disorders.