The b-amyloid peptide Ab.is deposited in neuritic plaques which are characteristic features of Alzheimer's disease AD.. Prominent neurodegeneration and glial activation occurs around these plaques leading to the hypothesis that Ab may play a causative role in the neuronal loss and the inflammatory response associated with AD. Here we show that Ab-induced toxicity of cultured fetal rat cortical neurons is associated with internucleosomal DNA fragmentation beginning just 6 h after neurons are exposed to Ab. Additionally, constitutive NF-k B activity readily measured in fetal rat cortical neurons decreases in a concentration-and time-dependent fashion following exposure to Ab, but there is no corresponding decrease in NF-k B mRNA or protein p65.. An upregulation of both Ik Ba protein and mRNA which occurs in cortical neurons exposed to Ab may be responsible for retaining NF-k B in the cytoplasm accounting for the observed decrease in activated NF-k B. The latter is supported by the observation that pretreatment of cortical cultures with an antisense oligonucleotide to Ik Ba mRNA is neuroprotective. In contrast to cortical neurons, exposure of rat primary astroglial cultures to Ab results in a concentration-and time-dependent activation of NF-k B with subsequent upregulation of IL-1b and IL-6. Our data suggest that Ab-induced neurotoxicity as well as astrocyte activation may be medicated by the NF-k BrRel family of proteins, and thus alterations in NF-k B-directed gene expression may contribute to both the neurodegeneration and inflammatory response which occur in AD.