Portal de Periódicos da CAPES

The NF-κB/Rel family of proteins mediates Aβ-induced neurotoxicity and glial activation

1998; Elsevier BV; Volume: 57; Issue: 1 Linguagem: Inglês

10.1016/s0169-328x(98)00066-7

1872-6941

Kelly R. Bales, Yansheng Du, Richard C. Dodel, Guang-Mei Yan, Elizabeth Hamilton‐Byrd, Steven M. Paul,

Immune Response and Inflammation

The β-amyloid peptide (Aβ) 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 Aβ may play a causative role in the neuronal loss and the inflammatory response associated with AD. Here we show that Aβ-induced toxicity of cultured fetal rat cortical neurons is associated with internucleosomal DNA fragmentation beginning just 6 h after neurons are exposed to Aβ. Additionally, constitutive NF-κB activity readily measured in fetal rat cortical neurons decreases in a concentration- and time-dependent fashion following exposure to Aβ, but there is no corresponding decrease in NF-κB mRNA or protein (p65). An upregulation of both IκBα protein and mRNA which occurs in cortical neurons exposed to Aβ may be responsible for retaining NF-κB in the cytoplasm accounting for the observed decrease in activated NF-κB. The latter is supported by the observation that pretreatment of cortical cultures with an antisense oligonucleotide to IκBα mRNA is neuroprotective. In contrast to cortical neurons, exposure of rat primary astroglial cultures to Aβ results in a concentration- and time-dependent activation of NF-κB with subsequent upregulation of IL-1β and IL-6. Our data suggest that Aβ-induced neurotoxicity as well as astrocyte activation may be medicated by the NF-κB/Rel family of proteins, and thus alterations in NF-κB-directed gene expression may contribute to both the neurodegeneration and inflammatory response which occur in AD.