Inhibition of NF-kappaB potentiates amyloid beta-mediated neuronal apoptosis.
One mechanism leading to neurodegeneration during Alzheimer's disease (AD) is amyloid beta peptide (Abeta) neurotoxicity. Abeta 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-kappaB is activated by low doses of Abeta only. Here we show that NF-kappaB activation leads to neuroprotection. In primary neurons we found that a pretreatment with 0.1 microM Abeta-(1-40) protects against neuronal death induced with 10 microM Abeta-(1-40). As a known neuroprotective agent we next analyzed the effect of tumor necrosis factor alpha (TNF-alpha). Maximal activation of NF-kappaB was found with 2 ng/ml TNF-alpha. Pretreatment with TNF-alpha protected cerebellar granule cells from cell death induced by 10 microM Abeta-(1-40). This protection is described by an inverted U-shaped dose response and is maximal with a NF-kappaB-activating dose. The molecular specificity of this protective effect was analyzed by specific blockade of NF-kappaB activation. Overexpression of a transdominant negative IkappaB-alpha blocks NF-kappaB activation and potentiates Abeta-mediated neuronal apoptosis. Our findings show that activation of NF-kappaB is the underlying mechanism of the neuroprotective effect of low-dose Abeta and TNF-alpha. In accordance with these in vitro data we find that nuclear NF-kappaB immunoreactivity around various plaque stages of AD patients is reduced in comparison to age-matched controls. Taken together these data suggest that pharmacological NF-kappaB activation may be a useful approach in the treatment of AD and related neurodegenerative disorders.
Kaltschmidt
B
B
Molecular Neurobiology Laboratory, Institute of Anatomy, Albert-Ludwigs-University, Stefan-Meier-Strasse 19, D-79104 Freiburg, Germany. kaltschm@ruf.uni-freiburg.de
Uherek
M
M
Wellmann
H
H
Volk
B
B
Kaltschmidt
C
C
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D058225:Plaque, Amyloid / Q000473:pathology; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D018696:Neuroprotective Agents; C000606206:Nfkbia protein, rat; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C078592:amyloid beta-protein (1-40); D000072000:NF-KappaB Inhibitor alpha