The NF-kappaB/Rel family of proteins mediates Abeta-induced neurotoxicity and glial activation.
The beta-amyloid peptide (Abeta) 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 Abeta may play a causative role in the neuronal loss and the inflammatory response associated with AD. Here we show that Abeta-induced toxicity of cultured fetal rat cortical neurons is associated with internucleosomal DNA fragmentation beginning just 6 h after neurons are exposed to Abeta. Additionally, constitutive NF-kappaB activity readily measured in fetal rat cortical neurons decreases in a concentration- and time-dependent fashion following exposure to Abeta, but there is no corresponding decrease in NF-kappaB mRNA or protein (p65). An upregulation of both IkappaB alpha protein and mRNA which occurs in cortical neurons exposed to Abeta may be responsible for retaining NF-kappaB in the cytoplasm accounting for the observed decrease in activated NF-kappaB. The latter is supported by the observation that pretreatment of cortical cultures with an antisense oligonucleotide to IkappaBalpha mRNA is neuroprotective. In contrast to cortical neurons, exposure of rat primary astroglial cultures to Abeta results in a concentration- and time-dependent activation of NF-kappaB with subsequent upregulation of IL-1beta and IL-6. Our data suggest that Abeta-induced neurotoxicity as well as astrocyte activation may be medicated by the NF-kappaB/Rel family of proteins, and thus alterations in NF-kappaB-directed gene expression may contribute to both the neurodegeneration and inflammatory response which occur in AD.
Bales
K R
KR
Neuroscience Discovery Research, Eli Lilly, Indianapolis, IN 46285, USA.
Du
Y
Y
Dodel
R C
RC
Yan
G M
GM
Hamilton-Byrd
E
E
Paul
S M
SM
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D007375:Interleukin-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology*; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D009498:Neurotoxins / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel; D051381:Rats
D016229:Amyloid beta-Peptides; D016375:Antisense Elements (Genetics); D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D009498:Neurotoxins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; C078592:amyloid beta-protein (1-40); D011505:Protein-Tyrosine Kinases